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Pamies A, Vallvé JC, Paredes S. New Cardiovascular Risk Biomarkers in Rheumatoid Arthritis: Implications and Clinical Utility-A Narrative Review. Biomedicines 2025; 13:870. [PMID: 40299461 PMCID: PMC12025197 DOI: 10.3390/biomedicines13040870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 03/28/2025] [Accepted: 04/02/2025] [Indexed: 04/30/2025] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease that not only causes joint inflammation but also significantly increases the risk of cardiovascular disease (CVD), leading to a higher morbidity and mortality. RA patients face an accelerated progression of atherosclerosis, attributed to both traditional cardiovascular risk factors and systemic inflammation. This review focuses on emerging biomarkers for cardiovascular risk assessment in RA, aiming to enhance early detection and treatment strategies. Specifically, we examine the roles of interleukin-32 (IL-32), Dickkopf-1 (DKK-1), galectin-3 (Gal-3), catestatin (CST), and fetuin-A (Fet-A) as potential markers for CVD in this patient population. IL-32, a proinflammatory cytokine, is elevated in RA patients and plays a significant role in inflammation and endothelial dysfunction, both of which contribute to atherosclerosis. DKK-1, a Wnt signaling pathway inhibitor, has been associated with both synovial inflammation and the development of atherosclerotic plaques. Elevated DKK-1 levels have been linked to an increased CV mortality and could serve as a marker for CVD progression in RA. Gal-3 is involved in immune modulation and fibrosis, with elevated levels in RA patients correlating with disease activity and cardiovascular outcomes. Catestatin, a peptide derived from chromogranin A, has protective anti-inflammatory and antioxidative properties, though its role in RA-related CVD remains under investigation. Finally, Fet-A, a glycoprotein involved in vascular calcification, shows potential as a biomarker for CV events in RA, though data on its role remain conflicting. These biomarkers provide deeper insights into the pathophysiology of RA and its cardiovascular comorbidities. Although some biomarkers show promise in improving CV risk stratification, further large-scale studies are required to validate their clinical utility. Currently, these biomarkers are in the research phase and are not yet implemented in standard care. Identifying and incorporating these biomarkers into routine clinical practice could lead to the better management of cardiovascular risk in RA patients, thus improving outcomes in this high-risk population. This review highlights the importance of continued research to establish reliable biomarkers that can aid in both diagnosis and the development of targeted therapies for cardiovascular complications in RA.
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Affiliation(s)
- Anna Pamies
- Secció de Reumatologia, Hospital de Tortosa Verge de la Cinta, 43500 Tortosa, Catalonia, Spain;
| | - Joan-Carles Vallvé
- Unitat de Recerca en Lípids i Arterioesclerosi, Universitat Rovira i Virgili, 43204 Reus, Catalonia, Spain;
- Institut Investigació Sanitaria Pere Virgili, 43204 Reus, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Silvia Paredes
- Unitat de Recerca en Lípids i Arterioesclerosi, Universitat Rovira i Virgili, 43204 Reus, Catalonia, Spain;
- Institut Investigació Sanitaria Pere Virgili, 43204 Reus, Catalonia, Spain
- Secció de Reumatologia, Hospital Universitari Sant Joan de Reus, 43204 Reus, Catalonia, Spain
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Sang X, Xue X, Mi Z, Wang Z, Yu X, Sun L, Ma S, Wang Z, Liu H, Zhang F. Induction of IL-32 in the immune response of keratinocytes to Mycobacterium marinum infection. Exp Dermatol 2023; 32:1451-1458. [PMID: 37309674 DOI: 10.1111/exd.14848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 06/14/2023]
Abstract
Keratinocytes are the predominant cell type in the skin epidermis, and they not only protect the skin from the influence of external physical factors but also function as an immune barrier against microbial invasion. However, little is known regarding the immune defence mechanisms of keratinocytes against mycobacteria. Here, we performed single-cell RNA sequencing (scRNA-seq) on skin biopsy samples from patients with Mycobacterium marinum infection and bulk RNA sequencing (bRNA-seq) on M. marinum-infected keratinocytes in vitro. The combined analysis of scRNA-seq and bRNA-seq data revealed that several genes were upregulated in M. marinum-infected keratinocytes. Further in vitro validation of these genes by quantitative polymerase chain reaction and western blotting assay confirmed the induction of IL-32 in the immune response of keratinocytes to M. marinum infection. Immunohistochemistry also showed the high expression of IL-32 in patients' lesions. These findings suggest that IL-32 induction is a possible mechanism through which keratinocytes defend against M. marinum infection; this could provide new targets for the immunotherapy of chronic cutaneous mycobacterial infections.
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Affiliation(s)
- Xu Sang
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Xiaotong Xue
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Zihao Mi
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Zhenzhen Wang
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Xueping Yu
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Lele Sun
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Shanshan Ma
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Zhe Wang
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Hong Liu
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Furen Zhang
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
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Chwastek J, Kędziora M, Borczyk M, Korostyński M, Starowicz K. Inflammation-Driven Secretion Potential Is Upregulated in Osteoarthritic Fibroblast-Like Synoviocytes. Int J Mol Sci 2022; 23:ijms231911817. [PMID: 36233118 PMCID: PMC9570304 DOI: 10.3390/ijms231911817] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/24/2022] [Accepted: 09/30/2022] [Indexed: 11/25/2022] Open
Abstract
Osteoarthritis (OA) is one of the most common joint pathologies and a major cause of disability among the population of developed countries. It manifests as a gradual degeneration of the cartilage and subchondral part of the bone, leading to joint damage. Recent studies indicate that not only the cells that make up the articular cartilage but also the synoviocytes, which build the membrane surrounding the joint, contribute to the development of OA. Therefore, the aim of the study was to determine the response to inflammatory factors of osteoarthritic synoviocytes and to identify proteins secreted by them that may influence the progression of OA. This study demonstrated that fibroblast-like synoviocytes of OA patients (FLS-OA) respond more strongly to pro-inflammatory stimulation than cells obtained from control patients (FLS). These changes were observed at the transcriptome level and subsequently confirmed by protein analysis. FLS-OA stimulated by pro-inflammatory factors [such as lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα) were shown to secrete significantly more chemokines (CXCL6, CXCL10, and CXCL16) and growth factors [angiopoietin-like protein 1 (ANGPTL1), fibroblast growth factor 5 (FGF5), and insulin-like growth factor 2 (IGF2)] than control cells. Moreover, the translation of proteolytic enzymes [matrix metalloprotease 3 (MMP3), cathepsin K (CTSK), and cathepsin S (CTSS)] by FLS-OA is increased under inflammatory conditions. Our data indicate that the FLS of OA patients are functionally altered, resulting in an enhanced response to the presence of pro-inflammatory factors in the environment, manifested by the increased production of the previously mentioned proteins, which may promote further disease progression.
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Affiliation(s)
- Jakub Chwastek
- Department of Neurochemistry, Maj Institute of Pharmacology Polish Academy of Sciences, 31-343 Krakow, Poland
| | - Marta Kędziora
- Department of Neurochemistry, Maj Institute of Pharmacology Polish Academy of Sciences, 31-343 Krakow, Poland
| | - Małgorzata Borczyk
- Laboratory of Pharmacogenomics, Department of Molecular Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 31-343 Krakow, Poland
| | - Michał Korostyński
- Laboratory of Pharmacogenomics, Department of Molecular Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 31-343 Krakow, Poland
| | - Katarzyna Starowicz
- Department of Neurochemistry, Maj Institute of Pharmacology Polish Academy of Sciences, 31-343 Krakow, Poland
- Correspondence:
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Liu QH, Zhang JW, Xia L, Wise SG, Hambly BD, Tao K, Bao SS. Clinical implications of interleukins-31, 32, and 33 in gastric cancer. World J Gastrointest Oncol 2022; 14:1808-1822. [PMID: 36187404 PMCID: PMC9516641 DOI: 10.4251/wjgo.v14.i9.1808] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/21/2022] [Accepted: 07/31/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignancies in China with a high morbidity and mortality. AIM To determine whether interleukin (IL)-31, IL-32, and IL-33 can be used as biomarkers for the detection of GC, via evaluating the correlations between their expression and clinicopathological parameters of GC patients. METHODS Tissue array (n = 180) gastric specimens were utilised. IL-31, IL-32, and IL-33 expression in GC and non-GC tissues was detected immunohistochemically. The correlations between IL-31, IL-32, and IL-33 expression in GC and severity of clinicopathological parameters were evaluated. Survival curves were plotted using the Kaplan-Meier method/Cox regression. Circulating IL-31, IL-32, and IL-33 were detected by ELISA. RESULTS We found that the expression levels of IL-31, IL-32, and IL-33 were all lower in GC than in adjacent non-GC gastric tissues (P < 0.05). IL-33 in peripheral blood of GC patients was significantly lower than that of healthy individuals (1.50 ± 1.11 vs 9.61 ± 8.00 ng/mL, P <0.05). Decreased IL-31, IL-32, and IL-33 in GC were observed in younger patients (< 60 years), and IL-32 and IL-33 were lower in female patients (P < 0.05). Higher IL-32 correlated with a longer survival in two GC subgroups: T4 invasion depth and TNM I-II stage. Univariate/multivariate analysis revealed that IL-32 was an independent prognostic factor for GC in the T4 stage subgroup. Circulating IL-33 was significantly lower in GC patients at TNM stage IV than in healthy people (P < 0.05). CONCLUSION Our findings may provide new insights into the roles of IL-31, IL-32, and IL-33 in the carcinogenesis of GC and demonstrate their relative usefulness as prognostic markers for GC. The underlying mechanism of IL-31, IL-32, and IL-33 actions in GC should be further explored.
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Affiliation(s)
- Qing-Hua Liu
- Department of Pathology, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Ji-Wei Zhang
- Department of Surgery, The Central Hospital of Songjiang District, Shanghai Jiaotong University, Shanghai 201699, Shanghai, China
| | - Lei Xia
- Department of Pathology, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Steven G Wise
- Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Sydney 2006, NSW, Australia
| | | | - Kun Tao
- Department of Pathology,Tongren Hospital, Shanghai 200336, China
| | - Shi-San Bao
- Department of Pathology,Tongren Hospital, Shanghai 200336, China
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Extracellular vesicle IL-32 promotes the M2 macrophage polarization and metastasis of esophageal squamous cell carcinoma via FAK/STAT3 pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:145. [PMID: 35428295 PMCID: PMC9013041 DOI: 10.1186/s13046-022-02348-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 03/26/2022] [Indexed: 01/02/2023]
Abstract
Background Metastasis is the leading cause of mortality in human cancers, including esophageal squamous cell carcinoma (ESCC). As a pro-inflammatory cytokine, IL-32 was reported to be a poor prognostic factor in many cancers. However, the role of IL-32 in ESCC metastasis remains unknown. Methods ESCC cells with ectopic expression or knockdown of IL-32 were established and their effects on cell motility were detected. Ultracentrifugation, Transmission electron microscopy and Western blot were used to verify the existence of extracellular vesicle IL-32 (EV-IL-32). Coculture assay, immunofluorescence, flow cytometry, and in vivo lung metastasis model were performed to identify how EV-IL-32 regulated the crosstalk between ESCC cells and macrophages. Results Here, we found that IL-32 was overexpressed and positively correlated to lymph node metastasis of ESCC. IL-32 was significantly higher in the tumor nest compared with the non-cancerous tissue. We found that IL-32β was the main isoform and loaded in EV derived from ESCC cells. The shuttling of EV-IL-32 derived from ESCC cells into macrophages could promote the polarization of M2 macrophages via FAK-STAT3 pathway. IL-32 overexpression facilitated lung metastasis and was positively correlated with the proportion of M2 macrophages in tumor microenvironment. Conclusions Taken together, our results indicated that EV-IL-32 derived from ESCC cell line could be internalized by macrophages and lead to M2 macrophage polarization via FAK-STAT3 pathway, thus promoting the metastasis of ESCC. These findings indicated that IL-32 could serve as a potential therapeutic target in patients with ESCC. Supplementary information The online version contains supplementary material available at 10.1186/s13046-022-02348-8.
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Mohamed MS, Ghaly S, Azmy KH, Mohamed GA. Assessment of interleukin 32 as a novel biomarker for non-alcoholic fatty liver disease. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00189-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterised by enhanced hepatic fat deposition and inflammation. Efforts to manage NAFLD are limited by the poorly characterised pathological processes and the lack of precise non-invasive markers, thus, proving the need to further study the involved cytokines, which, in turn, may represent novel molecular targets with possible diagnostic and therapeutic applications. Hence, we aimed to assess the diagnostic utility of serum interleukin 32 (IL-32) in NAFLD cases. This case-control study included 40 NAFLD patients and 40 healthy controls. The serum IL-32 concentrations were assessed by the enzyme-linked immunosorbent assay (ELISA).
Results
The serum IL-32 concentrations were significantly higher in NAFLD cases than controls (76 [45.5–111.125] vs. 13 [8–15] pg/mL, P < 0.001, respectively). IL-32 at a cut-off point > 22.5 pg/mL had 100% sensitivity, 87.50% specificity, 88.9% positive predictive value, 100% negative predictive value, and 98.2% accuracy in detecting the NAFLD cases.
Conclusion
Serum IL-32 could be considered a novel non-invasive marker for NAFLD. Further investigations are warranted to verify the potential utility of IL-32 in the clinical setting.
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Ribeiro-Dias F, Oliveira I. A Critical Overview of Interleukin 32 in Leishmaniases. Front Immunol 2022; 13:849340. [PMID: 35309341 PMCID: PMC8927017 DOI: 10.3389/fimmu.2022.849340] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 02/11/2022] [Indexed: 12/22/2022] Open
Abstract
Interleukin-32 (IL-32) has several immune regulatory properties, which have driven its investigation in the context of various diseases. IL-32 expression is reported to be induced in the lesions of patients with American tegumentary leishmaniasis (ATL) by the New World Leishmania spp. that are responsible for causing ATL and visceral leishmaniasis (VL). IL-32 expression may elevate the inflammatory process through the induction of pro-inflammatory cytokines and also via mechanisms directed to kill the parasites. The genetic variants of IL-32 might be associated with the resistance or susceptibility to ATL, while different isoforms of IL-32 could be associated with distinct T helper lymphocyte profiles. IL-32 also determines the transcriptional profile in the bone marrow progenitor cells to mediate the trained immunity induced by β-glucan and BCG, thereby contributing to the resistance against Leishmania. IL-32γ is essential for the vitamin D-dependent microbicidal pathway for parasite control. In this context, the present review report briefly discusses the data retrieved from the studies conducted on IL-32 in leishmaniasis in humans and mice to highlight the current challenges to understanding the role of IL-32 in leishmaniasis.
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Affiliation(s)
- Fátima Ribeiro-Dias
- Laboratório de Imunidade Natural, Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Brazil
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Zhao J, Wei K, Chang C, Xu L, Jiang P, Guo S, Schrodi SJ, He D. DNA Methylation of T Lymphocytes as a Therapeutic Target: Implications for Rheumatoid Arthritis Etiology. Front Immunol 2022; 13:863703. [PMID: 35309322 PMCID: PMC8927780 DOI: 10.3389/fimmu.2022.863703] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 02/14/2022] [Indexed: 11/28/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease that can cause joint damage and disability. Epigenetic variation, especially DNA methylation, has been shown to be involved in almost all the stages of the pathology of RA, from autoantibody production to various self-effector T cells and the defects of protective T cells that can lead to chronic inflammation and erosion of bones and joints. Given the critical role of T cells in the pathology of RA, the regulatory functions of DNA methylation in T cell biology remain unclear. In this review, we elaborate on the relationship between RA pathogenesis and DNA methylation in the context of different T cell populations. We summarize the relevant methylation events in T cell development, differentiation, and T cell-related genes in disease prediction and drug efficacy. Understanding the epigenetic regulation of T cells has the potential to profoundly translate preclinical results into clinical practice and provide a framework for the development of novel, individualized RA therapeutics.
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Affiliation(s)
- Jianan Zhao
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Kai Wei
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Cen Chang
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Lingxia Xu
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Ping Jiang
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Shicheng Guo
- Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI, United States
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Steven J. Schrodi
- Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI, United States
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Dongyi He
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Arthritis Institute of Integrated Traditional and Western medicine, Shanghai Chinese Medicine Research Institute, Shanghai, China
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Shim S, Lee S, Hisham Y, Kim S, Nguyen TT, Taitt AS, Hwang J, Jhun H, Park HY, Lee Y, Yeom SC, Kim SY, Kim YG, Kim S. Comparison of the Seven Interleukin-32 Isoforms’ Biological Activities: IL-32θ Possesses the Most Dominant Biological Activity. Front Immunol 2022; 13:837588. [PMID: 35281066 PMCID: PMC8914309 DOI: 10.3389/fimmu.2022.837588] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/17/2022] [Indexed: 11/13/2022] Open
Abstract
Cytokines are significantly associated with the homeostasis of immune responses in health and disease. Interleukin-32 (IL-32) is a cytokine originally discovered in natural killer cell transcript 4. IL-32 with different disorders has been described in terms of pathogenesis and the progression of diseases. Clinical studies have investigated IL-32 under various conditions, such as viral infection, autoimmune diseases, inflammatory diseases, certain types of cancer, vascular disease, and pulmonary diseases. The high expression of IL-32 was identified in different tissues with various diseases and found to have multiple transcripts of up to seven isoforms. However, the purification and biological activities of these isoforms have not been investigated yet. Therefore, in this study, we purified and compared the biological activity of recombinant IL-32 (rIL-32) isoforms. This is the first time for seven rIL-32 isoforms (α, β, δ, γ, ϵ, ζ, and θ) to be cloned and purified using an Escherichia coli expression system. Next, we evaluate the biological activities of these seven rIL-32 isoforms, which were used to treat different types of cells by assessing the levels of inflammatory cytokine production. The results revealed that rIL-32θ possessed the most dominant biological activity in both immune and non-immune cells.
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Affiliation(s)
- Saerok Shim
- Laboratory of Cytokine Immunology, Department of Biomedical Science and Technology, Konkuk University, Seoul, South Korea
| | - Siyoung Lee
- Laboratory of Cytokine Immunology, Department of Biomedical Science and Technology, Konkuk University, Seoul, South Korea
| | - Yasmin Hisham
- Laboratory of Cytokine Immunology, Department of Biomedical Science and Technology, Konkuk University, Seoul, South Korea
| | - Sinae Kim
- Laboratory of Cytokine Immunology, Department of Biomedical Science and Technology, Konkuk University, Seoul, South Korea
- College of Veterinary Medicine, Konkuk University, Seoul, South Korea
| | - Tam T. Nguyen
- Laboratory of Cytokine Immunology, Department of Biomedical Science and Technology, Konkuk University, Seoul, South Korea
- College of Veterinary Medicine, Konkuk University, Seoul, South Korea
| | - Afeisha S. Taitt
- Laboratory of Cytokine Immunology, Department of Biomedical Science and Technology, Konkuk University, Seoul, South Korea
| | - Jihyeong Hwang
- Laboratory of Cytokine Immunology, Department of Biomedical Science and Technology, Konkuk University, Seoul, South Korea
| | - Hyunjhung Jhun
- Technical Assistance Center, Korea Food Research Institute, Wanju, South Korea
| | - Ho-Young Park
- Research Group of Functional Food Materials, Korea Food Research Institute, Wanju, South Korea
| | - Youngmin Lee
- Department of Medicine, Pusan Paik Hospital, Collage of Medicine, Inje University, Busan, South Korea
| | - Su Cheong Yeom
- Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, South Korea
| | - Sang-Yeob Kim
- Convergence Medicine Research Center, Asan Institute for Life Science, Asan Medical Center, Seoul, South Korea
| | - Yong-Gil Kim
- Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
- *Correspondence: Yong-Gil Kim, ; Soohyun Kim,
| | - Soohyun Kim
- Laboratory of Cytokine Immunology, Department of Biomedical Science and Technology, Konkuk University, Seoul, South Korea
- College of Veterinary Medicine, Konkuk University, Seoul, South Korea
- *Correspondence: Yong-Gil Kim, ; Soohyun Kim,
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Hamzaoui K, Borhani-Haghighi A, Dhifallah IB, Hamzaoui A. Elevated levels of IL-32 in cerebrospinal fluid of neuro-Behcet disease: Correlation with NLRP3 inflammasome. J Neuroimmunol 2022; 365:577820. [DOI: 10.1016/j.jneuroim.2022.577820] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 01/10/2022] [Accepted: 01/16/2022] [Indexed: 12/14/2022]
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Ren P, Lu L, Cai S, Chen J, Lin W, Han F. Alternative Splicing: A New Cause and Potential Therapeutic Target in Autoimmune Disease. Front Immunol 2021; 12:713540. [PMID: 34484216 PMCID: PMC8416054 DOI: 10.3389/fimmu.2021.713540] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 07/29/2021] [Indexed: 11/13/2022] Open
Abstract
Alternative splicing (AS) is a complex coordinated transcriptional regulatory mechanism. It affects nearly 95% of all protein-coding genes and occurs in nearly all human organs. Aberrant alternative splicing can lead to various neurological diseases and cancers and is responsible for aging, infection, inflammation, immune and metabolic disorders, and so on. Though aberrant alternative splicing events and their regulatory mechanisms are widely recognized, the association between autoimmune disease and alternative splicing has not been extensively examined. Autoimmune diseases are characterized by the loss of tolerance of the immune system towards self-antigens and organ-specific or systemic inflammation and subsequent tissue damage. In the present review, we summarized the most recent reports on splicing events that occur in the immunopathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and attempted to clarify the role that splicing events play in regulating autoimmune disease progression. We also identified the changes that occur in splicing factor expression. The foregoing information might improve our understanding of autoimmune diseases and help develop new diagnostic and therapeutic tools for them.
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Affiliation(s)
- Pingping Ren
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Luying Lu
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Shasha Cai
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Nephrology, The First People’s Hospital of Wenling, Taizhou, China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Weiqiang Lin
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
- Institute of Translational Medicine, Zhejiang University of Medicine, Hangzhou, China
| | - Fei Han
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
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Impact of interleukin-32 germ-line rs28372698 and intronic rs12934561 polymorphisms on cancer development: A systematic review and meta-analysis. Int Immunopharmacol 2021; 99:107964. [PMID: 34271417 DOI: 10.1016/j.intimp.2021.107964] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/21/2021] [Accepted: 07/05/2021] [Indexed: 11/24/2022]
Abstract
OBJECTIVE The pro-inflammatory cytokine IL-32 has high susceptibility to develop cancer. But no previous meta-analysis was done to provide firm evidence. This systematic review and meta-analysis was designed to evaluate the association of IL-32 gene polymorphisms (rs28372698 and rs12934561) with cancer. METHOD Eligible studies were selected using authentic databases searching from January 2013 to January 2021. Demographic data and genotypic information were extracted and organized from the selected studies. Review Manager (RevMan) version 5.4 was used to perform data analysis and data arrangement for meta-analysis. RESULTS A total of seven studies with 3395 patients and 3781 controls were included in this study. IL-32 rs28372698 polymorphism implied that mutant allele (TT) carriers had a significantly higher risk of cancer (OR = 1.43, p = 0.032). Codominant 3, recessive and allele models also showed 1.36-, 1.38- and 1.11-fold increased risk, respectively (p < 0.05). Besides, the Asian population showed a significantly increased risk in codominant 2 (OR = 1.74), codominant 3 (OR = 1.78), recessive (OR = 1.76) and allele model (OR = 1.16). IL-32 rs12934561 showed significantly reduced cancer risk in codominant 1 (OR = 0.66. p = 0.035), codominant 2 (OR = 0.76, p = 0.007), and dominant model (OR = 0.72, p = 0.012). After subgroup analysis, an association of rs12934561 was found in Asians (codominant 1: OR = 0.54, p = 7.28 × 10-8; codominant 2: OR = 1.40, p = 0.019; codominant 3: OR = 0.76, p = 0.0006; dominant model: OR = 0.64, p = 1.12 × 10-5; overdominant model: OR = 0.64, p = 3.92 × 10-7) but not in Caucasians. After stratifying with the control source, a significant (p < 0.05) association of rs28372698 and rs12934561 was found with cancer in population-based controls. No publication bias was found, and the outcome of this meta-analysis was not influenced by any individual study confirmed from sensitivity analysis. Moreover, trial sequential analysis (TSA) established a link between rs28372698 and rs12934561 polymorphisms and cancer. CONCLUSION The outcome of this meta-analysis revealed that IL-32 rs28372698 and rs12934561 polymorphisms are associated with cancer. Moreover, the Asian dynasty had a significant association compared to Caucasians.
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Ma Z, Dong Z, Yu D, Mu M, Feng W, Guo J, Cheng B, Guo J, Ma J. IL-32 Promotes the Radiosensitivity of Esophageal Squamous Cell Carcinoma Cell through STAT3 Pathway. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6653747. [PMID: 33681363 PMCID: PMC7904356 DOI: 10.1155/2021/6653747] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 12/30/2020] [Indexed: 12/28/2022]
Abstract
OBJECTIVE This study is set out to determine the relationship between IL-32 and radiosensitivity of esophageal squamous cell carcinoma (ESCC). METHODS Western blot was adopted for measuring IL-32 expression in Eca-109 and TE-10 cells. Eca-109 and TE-10 cells with interference or overexpression of IL-32 were treated with the presence or absence of X-ray irradiation. Then, the use of CCK8 assay was to detect proliferation ability, and effects of IL-32 expression on radiosensitivity of ESCC were tested by colony formation assay. The cell apoptosis was detected using flow cytometry. STAT3 and p-STAT expression, and apoptotic protein Bax were detected by western blot. RESULTS Colony formation assay and CCK8 assay showed that compared with the NC group without treatment, the growth of the ESCC cells, that is Eca-109 and TE-10, was significantly inhibited in the OE+IR group with highly expressed IL-32 and irradiation. In flow cytometry analysis, in Eca-109 and TE-10 cells, highly expressed IL-32 combined with irradiation significantly increased apoptosis compared with the control group. Highly expressed IL-32 has a synergistic effect with irradiation, inhibiting STAT3 and p-STAT3 expression and increasing apoptotic protein Bax expression. CONCLUSION IL-32 can improve the radiosensitivity of ESCC cells by inhibiting the STAT3 pathway. Therefore, IL-32 can be used as a new therapeutic target to provide a new attempt for radiotherapy of ESCC.
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Affiliation(s)
- Zhiyu Ma
- First Department of Radiotherapy, Wanbei Coal-Electricity Group General Hospital, Suzhou, 234000 Anhui, China
| | - Zhen Dong
- Department of Radiotherapy, BenQ Medical Center Affiliated to Nanjing Medical University, Nanjing, 210000 Jiangsu, China
| | - Dingyue Yu
- Department of Radiotherapy, Bengbu Second People's Hospital Affiliated to Bengbu Medical Collage, Bengbu, 233000 Anhui, China
| | - Mingchen Mu
- Department of Radiotherapy, Lianyungang Municipal Oriental Hospital Affiliated to Bengbu Medical Collage, Lianyungang, 222042 Jiangsu, China
| | - Wanwen Feng
- Translational Medicine Center, Lianyungang Municipal Oriental Hospital Affiliated to Bengbu Medical Collage, Lianyungang, 222042 Jiangsu, China
| | - Jiayi Guo
- Department of Radiotherapy, Lianyungang Municipal Oriental Hospital Affiliated to Bengbu Medical Collage, Lianyungang, 222042 Jiangsu, China
| | - Beibei Cheng
- Department of Radiotherapy, Lianyungang Municipal Oriental Hospital Affiliated to Bengbu Medical Collage, Lianyungang, 222042 Jiangsu, China
| | - Jiayou Guo
- Department of Radiotherapy, Lianyungang Municipal Oriental Hospital Affiliated to Bengbu Medical Collage, Lianyungang, 222042 Jiangsu, China
| | - Jianxin Ma
- Department of Radiotherapy, Lianyungang Municipal Oriental Hospital Affiliated to Bengbu Medical Collage, Lianyungang, 222042 Jiangsu, China
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14
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de Albuquerque R, Komsi E, Starskaia I, Ullah U, Lahesmaa R. The role of Interleukin-32 in autoimmunity. Scand J Immunol 2021; 93:e13012. [PMID: 33336406 DOI: 10.1111/sji.13012] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 11/28/2020] [Accepted: 12/12/2020] [Indexed: 01/10/2023]
Abstract
Interleukin-32 (IL-32) is a pro-inflammatory cytokine that induces other cytokines involved in inflammation, including tumour necrosis factor (TNF)-α, IL-6 and IL-1β. Recent evidence suggests that IL-32 has a crucial role in host defence against pathogens, as well as in the pathogenesis of chronic inflammation. Abnormal IL-32 expression has been linked to several autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel diseases, and a recent study suggested the importance of IL-32 in the pathogenesis of type 1 diabetes. However, despite accumulating evidence, many molecular characteristics of this cytokine, including the secretory route and the receptor for IL-32, remain largely unknown. In addition, the IL-32 gene is found in higher mammals but not in rodents. In this review, we outline the current knowledge of IL-32 biological functions, properties, and its role in autoimmune diseases. We particularly highlight the role of IL-32 in rheumatoid arthritis and type 1 diabetes.
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Affiliation(s)
- Rafael de Albuquerque
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Elina Komsi
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Inna Starskaia
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Ubaid Ullah
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Riitta Lahesmaa
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
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15
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Dos Santos JC, Barroso de Figueiredo AM, Teodoro Silva MV, Cirovic B, de Bree LCJ, Damen MSMA, Moorlag SJCFM, Gomes RS, Helsen MM, Oosting M, Keating ST, Schlitzer A, Netea MG, Ribeiro-Dias F, Joosten LAB. β-Glucan-Induced Trained Immunity Protects against Leishmania braziliensis Infection: a Crucial Role for IL-32. Cell Rep 2020; 28:2659-2672.e6. [PMID: 31484076 DOI: 10.1016/j.celrep.2019.08.004] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 06/04/2019] [Accepted: 07/30/2019] [Indexed: 01/11/2023] Open
Abstract
American tegumentary leishmaniasis is a vector-borne parasitic disease caused by Leishmania protozoans. Innate immune cells undergo long-term functional reprogramming in response to infection or Bacillus Calmette-Guérin (BCG) vaccination via a process called trained immunity, conferring non-specific protection from secondary infections. Here, we demonstrate that monocytes trained with the fungal cell wall component β-glucan confer enhanced protection against infections caused by Leishmania braziliensis through the enhanced production of proinflammatory cytokines. Mechanistically, this augmented immunological response is dependent on increased expression of interleukin 32 (IL-32). Studies performed using a humanized IL-32 transgenic mouse highlight the clinical implications of these findings in vivo. This study represents a definitive characterization of the role of IL-32γ in the trained phenotype induced by β-glucan or BCG, the results of which improve our understanding of the molecular mechanisms governing trained immunity and Leishmania infection control.
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Affiliation(s)
- Jéssica Cristina Dos Santos
- Radboud Institute for Molecular Sciences (RILMS), Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | | | | | - Branko Cirovic
- Myeloid Cell Biology, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany
| | - L Charlotte J de Bree
- Radboud Institute for Molecular Sciences (RILMS), Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; Odense Patient Data Explorative Network, University of Southern Denmark and Odense University Hospital, Odense, Denmark
| | - Michelle S M A Damen
- Radboud Institute for Molecular Sciences (RILMS), Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Simone J C F M Moorlag
- Radboud Institute for Molecular Sciences (RILMS), Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Rodrigo S Gomes
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Monique M Helsen
- Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Marije Oosting
- Radboud Institute for Molecular Sciences (RILMS), Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Samuel T Keating
- Radboud Institute for Molecular Sciences (RILMS), Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - A Schlitzer
- Myeloid Cell Biology, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany; Single Cell Genomics and Epigenomics Unit at the German Center for Neurodegenerative Diseases and the University of Bonn, 53175 Bonn, Germany
| | - Mihai G Netea
- Radboud Institute for Molecular Sciences (RILMS), Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Germany
| | - Fátima Ribeiro-Dias
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brazil.
| | - Leo A B Joosten
- Radboud Institute for Molecular Sciences (RILMS), Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brazil.
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16
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Öngöz Dede F, Gökmenoğlu C, Deveci ET, Çelen S, Avci B, Kara C, Çanakçi V. Increased levels of interleukin-32 isoforms alpha, beta, gamma, and delta in the gingival crevicular fluid and plasma of the patients with periodontitis. J Periodontal Res 2020; 56:83-92. [PMID: 32890410 DOI: 10.1111/jre.12796] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 07/10/2020] [Accepted: 08/07/2020] [Indexed: 11/28/2022]
Abstract
BACKGROUND AND OBJECTIVE Interleukin (IL)-32, which has been recently reported to be associated with periodontitis, has been suggested to have pleiotropic effect due to its 9 different isoforms. The aim of this study was to investigate the levels of IL-32α, IL-32β, IL-32γ, IL-32δ isoforms in gingival crevicular fluid (GCF) and plasma before and after non-surgical periodontal treatment in patients with periodontitis (P). MATERIALS AND METHODS Twenty-seven P and 27 periodontally healthy controls (C) were recruited in this study. Non-surgical periodontal treatment was performed to periodontitis patients. GCF and plasma sampling and clinical periodontal parameters were evaluated before and 1 month after treatment. Enzyme-linked immunosorbent assay was used to analyze the levels of IL-32α, IL-32β, IL-32γ, IL-32δ isoforms in GCF and plasma samples. RESULTS The levels of IL-32α, IL-32β, IL-32γ, and IL-32δ in plasma and GCF were significantly higher in patients with periodontitis than healthy controls (P < .001). In P group, plasma and GCF IL-32α, IL-32β, IL-32γ, and IL-32δ levels after non-surgical periodontal treatment were lower when compared to baseline (P < .001). Moreover, there was a positive correlation between GCF and plasma IL-32α, IL-32β, IL-32γ, and IL-32δ levels in all groups at baseline and after treatment (P < .05). CONCLUSION The study supported that there was a relationship between elevated levels of IL-32 isoforms and periodontitis. Also, our novel findings suggest that the pro-inflammatory role of IL-32 in the periodontitis may be originated from IL-32α, IL-32β, IL-32γ, and IL-32δ isoforms.
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Affiliation(s)
- Figen Öngöz Dede
- Department of Periodontology, Faculty of Dentistry, Ordu University, Ordu, Turkey
| | - Ceren Gökmenoğlu
- Department of Periodontology, Faculty of Dentistry, Ordu University, Ordu, Turkey
| | - Emre Taha Deveci
- Department of Periodontology, Faculty of Dentistry, Ordu University, Ordu, Turkey
| | - Selman Çelen
- Department of Periodontology, Faculty of Dentistry, Ordu University, Ordu, Turkey
| | - Bahattin Avci
- Department of Medical Biochemistry, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
| | - Cankat Kara
- Department of Periodontology, Faculty of Dentistry, Ordu University, Ordu, Turkey
| | - Varol Çanakçi
- Department of Periodontology, Faculty of Dentistry, Ordu University, Ordu, Turkey
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17
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Aass KR, Kastnes MH, Standal T. Molecular interactions and functions of IL-32. J Leukoc Biol 2020; 109:143-159. [PMID: 32869391 DOI: 10.1002/jlb.3mr0620-550r] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 06/29/2020] [Accepted: 07/28/2020] [Indexed: 12/16/2022] Open
Abstract
IL-32 is a multifaceted cytokine associated with several diseases and inflammatory conditions. Its expression is induced in response to cellular stress such as hypoxia, infections, and pro-inflammatory cytokines. IL-32 can be secreted from cells and can induce the production of pro-inflammatory cytokines from several cell types but are also described to have anti-inflammatory functions. The intracellular form of IL-32 is shown to play an important role in various cellular processes, including the defense against intracellular bacteria and viruses and in modulation of cell metabolism. In this review, we discuss current literature on molecular interactions of IL-32 with other proteins. We also review data on the role of intracellular IL-32 as a metabolic regulator and its role in antimicrobial host defense.
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Affiliation(s)
- Kristin Roseth Aass
- Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research (CEMIR), Trondheim, Norway
| | - Martin H Kastnes
- Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research (CEMIR), Trondheim, Norway
| | - Therese Standal
- Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research (CEMIR), Trondheim, Norway.,Department of Hematology, St. Olavs Hospital, Trondheim, Norway
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18
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Bengts S, Shamoun L, Kunath A, Appelgren D, Welander M, Björck M, Wanhainen A, Wågsäter D. Altered IL-32 Signaling in Abdominal Aortic Aneurysm. J Vasc Res 2020; 57:236-244. [PMID: 32434199 DOI: 10.1159/000507667] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 04/02/2020] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION AND OBJECTIVE Interleukin (IL)-32 is a pro-inflammatory cytokine not previously studied in relation to abdominal aortic aneurysm (AAA). The aim of this study was to elucidate the expression and localization of IL-32 in AAA. METHODS Expression and localization of IL-32 in human aortic tissue was studied with immunohistochemical analysis and Western blot (AAA: n = 5; controls: n = 4). ELISA was used to measure IL-32 in human plasma samples (AAA: n = 140; controls: n = 37) and in media from cultured peripheral blood mononuclear cells (PBMCs) from 3 healthy donors. IL-32 mRNA in PBMCs, endothelial cells, aortic smooth muscle cells (SMCs), and aortic tissue samples of AAA (n = 16) and control aortas (n = 9) was measured with qPCR. RESULTS IL-32 was predominantly expressed in SMCs and T-cell-rich areas. Highest mRNA expression was observed in the intima/media layer of the AAA. A weaker protein expression was detected in non-aneurysmal aortas. Expression of IL-32 was confirmed in isolated T cells, macrophages, endothelial cells, and SMCs, where expression was also inducible by cytokines such as interferon-γ. There was no difference in IL-32 expression in plasma between patients and controls. CONCLUSION IL-32 signaling is altered locally in AAA and could potentially play an important role in aneurysm development. Further studies using animal models would be helpful to study its potential role in AAA disease.
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Affiliation(s)
- Sophy Bengts
- Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Levar Shamoun
- Division of Medical Diagnostics, Department of Laboratory Medicine, Jönköping County, Jönköping, Sweden.,Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Anne Kunath
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Daniel Appelgren
- Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Martin Welander
- Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Martin Björck
- Department of Surgical Sciences, Section of Vascular Surgery, Uppsala University, Uppsala, Sweden
| | - Anders Wanhainen
- Department of Surgical Sciences, Section of Vascular Surgery, Uppsala University, Uppsala, Sweden
| | - Dick Wågsäter
- Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden, .,Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden,
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Genetic variation in Interleukin-32 influence the immune response against New World Leishmania species and susceptibility to American Tegumentary Leishmaniasis. PLoS Negl Trop Dis 2020; 14:e0008029. [PMID: 32023240 PMCID: PMC7028298 DOI: 10.1371/journal.pntd.0008029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 02/18/2020] [Accepted: 01/03/2020] [Indexed: 02/07/2023] Open
Abstract
Interleukin-32 is a novel inflammatory mediator that has been described to be important in the immunopathogenesis and control of infections caused by Leishmania parasites. By performing experiments with primary human cells in vitro, we demonstrate that the expression of IL-32 isoforms is dependent on the time exposed to L. amazonensis and L. braziliensis antigens. Moreover, for the first time we show the functional consequences of three different genetic variations in the IL32 (rs4786370, rs4349147, rs1555001) modulating IL-32γ expression, influencing innate and adaptive cytokine production after Leishmania exposure. Using a Brazilian cohort of 107 American Tegumentary Leishmaniasis patients and a control cohort of 245 healthy individuals, the IL32 rs4786370 genetic variant was associated with protection against ATL, whereas the IL32 rs4349147 was associated with susceptibility to the development of localized cutaneous and mucosal leishmaniasis. These novel insights may help improve therapeutic strategies and lead to benefits for patients suffering from Leishmania infections. In this study, we described how IL-32 isoforms are crucial to host defense against new world Leishmania species infections. Furthermore, by accessing the genotype frequency of genetic variations in IL32 in a cohort of Brazilian patients with American Tegumentary Leishmaniasis (ATL) and controls, we have obtained indications that IL-32 is associated with disease susceptibility and the development of different clinical manifestations. Thus, this study provides us an extra evidence that the isoforms of IL-32 shape the immune response favoring the development of different cytokines produced by peripheral blood mononuclear cells that might contribute to skin/mucosal inflammation and host defense.
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Fadaei R, Bagheri N, Heidarian E, Nouri A, Hesari Z, Moradi N, Ahmadi A, Ahmadi R. Serum levels of IL-32 in patients with type 2 diabetes mellitus and its relationship with TNF-α and IL-6. Cytokine 2020; 125:154832. [DOI: 10.1016/j.cyto.2019.154832] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/24/2019] [Accepted: 08/24/2019] [Indexed: 10/26/2022]
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21
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Dali-Youcef N, Vix M, Costantino F, El-Saghire H, Lhermitte B, Callari C, D'Agostino J, Perretta S, Paveliu S, Gualtierotti M, Dumeny E, Oudot MA, Jaulin A, Dembélé D, Zeisel MB, Tomasetto C, Baumert TF, Doffoël M. Interleukin-32 Contributes to Human Nonalcoholic Fatty Liver Disease and Insulin Resistance. Hepatol Commun 2019; 3:1205-1220. [PMID: 31497742 PMCID: PMC6719754 DOI: 10.1002/hep4.1396] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 05/21/2019] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder due to increased accumulation of fat in the liver and in many cases to enhanced inflammation. Although the contribution of inflammation in the pathogenesis of NAFLD is well established, the cytokines that are involved and how they influence liver transformation are still poorly characterized. In addition, with other modifiers, inflammation influences NAFLD progression to liver cirrhosis and hepatocellular carcinoma, demonstrating the need to find new molecular targets with potential future therapeutic applications. We investigated gene signatures in 38 liver biopsies from patients with NAFLD and obesity who had received bariatric surgery and compared these to 10 control patients who had received a cholecystectomy, using DNA microarray technology. A subset of differentially expressed genes was then validated on a larger cohort of 103 patients who had received bariatric surgery for obesity; data were thoroughly analyzed in terms of correlations with NAFLD pathophysiological parameters. Finally, the impact of a specific cytokine, interleukin‐32 (IL32), was addressed on primary human hepatocytes (PHHs). Transcript analysis revealed an up‐regulation of proinflammatory cytokines IL32, chemokine (C‐X‐C motif) ligand 9 (CXCL9), and CXCL10 and of ubiquitin D (UBD), whereas down‐regulation of insulin‐like growth factor‐binding protein 2 (IGFBP2) and hypoxanthine phosphoribosyltransferase 1 (HPRT1) was reported in patients with NAFLD. Moreover, IL32, which is the major deregulated gene, correlated with body mass index (BMI), waist circumference, NAFLD activity score (NAS), aminotransferases (alanine aminotransferase [ALAT] and aspartate aminotransferase [ASAT]), and homeostasis model assessment of insulin resistance (HOMA‐IR) index in patients. Consistent with an instrumental role in the pathophysiology of NAFLD, treatment of control human hepatocytes with recombinant IL32 leads to insulin resistance, a hallmark metabolic deregulation in NAFLD hepatocytes. Conclusion:IL32 has a critical role in the pathogenesis of NAFLD and could be considered as a therapeutic target in patients.
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Affiliation(s)
- Nassim Dali-Youcef
- Laboratoire de Biochimie et Biologie Moléculaire, Pôle de Biologie Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg Strasbourg France.,Department of Functional Genomics and Cancer Institut de Génétique et de Biologie Moléculaire et Cellulaire/CNRS UMR 7104/INSERM U 1258/Université de Strasbourg Illkirch France
| | - Michel Vix
- Service de Chirurgie Digestive et Endocrinienne Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg Strasbourg France
| | - Federico Costantino
- Service de Chirurgie Digestive et Endocrinienne Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg Strasbourg France
| | - Houssein El-Saghire
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg Strasbourg France
| | - Benoit Lhermitte
- Department of Pathology Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg Strasbourg France
| | - Cosimo Callari
- Service de Chirurgie Digestive et Endocrinienne Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg Strasbourg France
| | - Jacopo D'Agostino
- Service de Chirurgie Digestive et Endocrinienne Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg Strasbourg France
| | - Silvana Perretta
- Service de Chirurgie Digestive et Endocrinienne Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg Strasbourg France
| | - Stefan Paveliu
- Service de Chirurgie Digestive et Endocrinienne Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg Strasbourg France
| | - Monica Gualtierotti
- Service de Chirurgie Digestive et Endocrinienne Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg Strasbourg France
| | - Edith Dumeny
- Service d'Anesthésie-Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg Strasbourg France
| | - Marine A Oudot
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg Strasbourg France
| | - Amélie Jaulin
- Department of Functional Genomics and Cancer Institut de Génétique et de Biologie Moléculaire et Cellulaire/CNRS UMR 7104/INSERM U 1258/Université de Strasbourg Illkirch France
| | - Doulaye Dembélé
- Microarray and Sequencing Platform Institut de Génétique et de Biologie Moléculaire et Cellulaire/CNRS UMR 7104/INSERM U 1258/Université de Strasbourg Illkirch France
| | - Mirjam B Zeisel
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg Strasbourg France
| | - Catherine Tomasetto
- Department of Functional Genomics and Cancer Institut de Génétique et de Biologie Moléculaire et Cellulaire/CNRS UMR 7104/INSERM U 1258/Université de Strasbourg Illkirch France
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg Strasbourg France.,Service d'Hépato-Gastroentérologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg Strasbourg France
| | - Michel Doffoël
- Service d'Hépato-Gastroentérologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg Strasbourg France
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22
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Interplay between thyroid cancer cells and macrophages: effects on IL-32 mediated cell death and thyroid cancer cell migration. Cell Oncol (Dordr) 2019; 42:691-703. [DOI: 10.1007/s13402-019-00457-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2019] [Indexed: 12/21/2022] Open
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23
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Zhao Z, Lan M, Li J, Dong Q, Li X, Liu B, Li G, Wang H, Zhang Z, Zhu B. The proinflammatory cytokine TNFα induces DNA demethylation-dependent and -independent activation of interleukin-32 expression. J Biol Chem 2019; 294:6785-6795. [PMID: 30824537 PMCID: PMC6497958 DOI: 10.1074/jbc.ra118.006255] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 02/21/2019] [Indexed: 12/16/2022] Open
Abstract
IL-32 is a cytokine involved in proinflammatory immune responses to bacterial and viral infections. However, the role of epigenetic events in the regulation of IL-32 gene expression is understudied. Here we show that IL-32 is repressed by DNA methylation in HEK293 cells. Using ChIP sequencing, locus-specific methylation analysis, CRISPR/Cas9-mediated genome editing, and RT-qPCR (quantitative RT-PCR) and immunoblot assays, we found that short-term treatment (a few hours) with the proinflammatory cytokine tumor necrosis factor α (TNFα) activates IL-32 in a DNA demethylation-independent manner. In contrast, prolonged TNFα treatment (several days) induced DNA demethylation at the promoter and a CpG island in the IL-32 gene in a TET (ten-eleven translocation) family enzyme- and NF-κB-dependent manner. Notably, the hypomethylation status of transcriptional regulatory elements in IL-32 was maintained for a long time (several weeks), causing elevated IL-32 expression even in the absence of TNFα. Considering that IL-32 can, in turn, induce TNFα expression, we speculate that such feedforward events may contribute to the transition from an acute inflammatory response to chronic inflammation.
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Affiliation(s)
- Zuodong Zhao
- From the Tsinghua University-Peking University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, China
- the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- the National Institute of Biological Sciences, Beijing 102206, China
| | - Mengying Lan
- the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- the College of Life Sciences, University of the Chinese Academy of Sciences, Beijing 100049, China, and
| | - Jingjing Li
- the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- the College of Life Sciences, University of the Chinese Academy of Sciences, Beijing 100049, China, and
| | - Qiang Dong
- the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiang Li
- the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Baodong Liu
- the State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Gang Li
- the Faculty of Health Sciences, University of Macau, Macau 999078, China
| | - Hailin Wang
- the State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Zhuqiang Zhang
- the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China,
| | - Bing Zhu
- the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China,
- the College of Life Sciences, University of the Chinese Academy of Sciences, Beijing 100049, China, and
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24
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Li Z, Wang Y, Liu X, Xing X, Zhang Y. Interleukin‐32ε induces caspase‐independent apoptosis mediated by N‐Myc interactor in macrophages infected with
Mycobacterium tuberculosis. FEBS J 2018; 286:572-583. [DOI: 10.1111/febs.14717] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 10/18/2018] [Accepted: 11/30/2018] [Indexed: 12/24/2022]
Affiliation(s)
- Zhongxia Li
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture College of Veterinary Medicine Northwest A&F University Yangling China
| | - Yizhi Wang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture College of Veterinary Medicine Northwest A&F University Yangling China
| | - Xin Liu
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture College of Veterinary Medicine Northwest A&F University Yangling China
| | - Xupeng Xing
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture College of Veterinary Medicine Northwest A&F University Yangling China
| | - Yong Zhang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture College of Veterinary Medicine Northwest A&F University Yangling China
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25
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Neupane S, Srivastav S, Bhurtel S, Katila N, Shadfar S, Park PH, Hong JT, Choi DY. Enhanced neuroinflammatory responses after systemic LPS injection in IL-32β transgenic mice. J Chem Neuroanat 2018; 94:173-182. [DOI: 10.1016/j.jchemneu.2018.07.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 07/16/2018] [Accepted: 07/20/2018] [Indexed: 12/12/2022]
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26
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The Biology and Role of Interleukin-32 in Tuberculosis. J Immunol Res 2018; 2018:1535194. [PMID: 30426023 PMCID: PMC6217754 DOI: 10.1155/2018/1535194] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 08/08/2018] [Accepted: 08/29/2018] [Indexed: 12/31/2022] Open
Abstract
Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading cause of morbidity and mortality globally, with nearly 10.4 million new cases of incidence and over 1.7 million deaths annually. Drug-resistant M. tuberculosis strains, especially multidrug-resistant or extensively drug-resistant strains, have further intensified the problem associated with tuberculosis control. Host-directed therapy is a promising alternative for tuberculosis control. IL-32 is increasingly recognized as an important host molecule against tuberculosis. In this review, we highlight the proinflammatory properties of IL-32 and the mode of action of IL-32 in mycobacterial infections to inspire the development of novel immunity-based countermeasures and host-directed therapies against tuberculosis.
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27
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Pfalzer AC, Leung K, Crott JW, Kim SJ, Tai AK, Parnell LD, Kamanu FK, Liu Z, Rogers G, Shea MK, Garcia PE, Mason JB. Incremental Elevations in TNFα and IL6 in the Human Colon and Procancerous Changes in the Mucosal Transcriptome Accompany Adiposity. Cancer Epidemiol Biomarkers Prev 2018; 27:1416-1423. [PMID: 30291114 DOI: 10.1158/1055-9965.epi-18-0121] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 05/31/2018] [Accepted: 08/16/2018] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Obesity, a risk factor for colorectal cancer, raises systemic levels of proinflammatory mediators. Whether increased levels also reside in the colons of obese individuals and are accompanied by procancerous alterations in the mucosal transcriptome is unknown. METHODS Concentrations of TNFα, IL1β, and IL6 in blood and colonic mucosa of 16 lean and 26 obese individuals were examined. Differences in the mucosal transcriptome between the two groups were defined. RESULTS Plasma IL6 and TNFα were 1.4- to 3-fold elevated in obese subjects [body mass index (BMI) ≥ 34 kg/m2] compared with the lean controls (P < 0.01). Among individuals with BMI ≥ 34 kg/m2 colonic concentrations of IL6 and TNFα were 2- to 3-fold greater than in lean subjects (P < 0.03). In a general linear model, adjusted for NSAID use, colonic IL6 (partial r = 0.41; P < 0.01) and TNFα (partial r = 0.41; P = 0.01) increased incrementally over the entire range of BMIs (18.1-45.7). Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with a reduction in colonic IL6 (β = -0.65, P < 0.02). RNA sequencing (NSAID users excluded) identified 182 genes expressed differentially between lean and obese subjects. The two gene networks most strongly linked to changes in expression included several differentially expressed genes known to regulate the procarcinogenic signaling pathways, NFκB and ERK 1/2, in a pattern consistent with upregulation of each in the obese subjects. CONCLUSIONS Incremental increases in two major proinflammatory colonic cytokines are associated with increasing BMI, and in the obese state are accompanied by procancerous changes in the transcriptome. IMPACT These observations delineate means by which an inflammatory milieu may contribute to obesity-promoted colon cancer.
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Affiliation(s)
- Anna C Pfalzer
- Vitamins & Carcinogenesis Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts.,Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts
| | - Keith Leung
- Vitamins & Carcinogenesis Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
| | - Jimmy W Crott
- Vitamins & Carcinogenesis Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
| | - Susan J Kim
- Vitamins & Carcinogenesis Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
| | - Albert K Tai
- Genomics Core, Tufts University School of Medicine, Boston, Massachusetts
| | - Laurence D Parnell
- Agricultural Research Service, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
| | - Frederick K Kamanu
- Nutrition and Genomics Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
| | - Zhenhua Liu
- School of Public Health and Health Sciences, University of Massachusetts, Amherst, Massachusetts
| | - Gail Rogers
- Nutritional Epidemiology Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
| | - M Kyla Shea
- Vitamin K Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
| | - Paloma E Garcia
- Vitamins & Carcinogenesis Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
| | - Joel B Mason
- Vitamins & Carcinogenesis Laboratory, The Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts. .,Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts.,Division of Gastroenterology, Tufts Medical Center, Boston, Massachusetts.,Division of Clinical Nutrition, Tufts Medical Center, Boston, Massachusetts
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28
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Xin T, Chen M, Duan L, Xu Y, Gao P. Interleukin-32: its role in asthma and potential as a therapeutic agent. Respir Res 2018; 19:124. [PMID: 29940981 PMCID: PMC6019726 DOI: 10.1186/s12931-018-0832-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 06/18/2018] [Indexed: 02/07/2023] Open
Abstract
Interleukin (IL)-32, also named natural killer cell transcript 4 (NK4), has increasingly been described as an immunoregulator that controls cell differentiation and cell death and is involved in the stimulation of anti−/pro-inflammatory cytokines. Abnormal presence of IL-32 has been repeatedly noticed during the pathogenesis of allergic, infectious, cancerous, and inflammatory diseases. Of particular note was the observation of the anti-inflammatory property of IL-32 in a murine ovalbumin model of allergic asthma. Compared to wild-type mice, IL-32γ transgenic mice show decreased levels of inflammatory cells, recruited eosinophils, and lymphocytes in bronchoalveolar lavage fluid in a mouse model of acute asthma. To date, the molecular mechanism underlying the role of IL-32 in asthma remains to be elucidated. This review aims to summarize recent advances in the pathophysiology of asthma and describe the links to IL-32. The possibilities of using IL-32 as an airway inflammation biomarker and an asthma therapeutic agent are also evaluated.
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Affiliation(s)
- Tong Xin
- Department of Respiratory Medicine, the Second Hospital of Jilin University, Changchun, Jilin, China
| | - Mo Chen
- Department of Respiratory Medicine, the Second Hospital of Jilin University, Changchun, Jilin, China
| | - Liwei Duan
- Department of Gastrointestinal medicine, the Second Hospital of Jilin University, Changchun, Jilin, China
| | - Yanling Xu
- Department of Geriatrics and General Medicine, the Second Hospital of Jilin University, Changchun, Jilin, China
| | - Peng Gao
- Department of Respiratory Medicine, the Second Hospital of Jilin University, Changchun, Jilin, China.
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29
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Abstract
Interleukin 32 (IL-32) is a proinflammatory cytokine involved in the development of several diseases, including cancer. IL-32 is a rather peculiar cytokine because its protein structure does not show resemblance with any of the known cytokines, and an IL-32 receptor to facilitate extracellular signaling has not yet been identified. Thus far, 9 isoforms of IL-32 have been described, all of which show differences in terms of effects and in potency to elicit a specific effect. Since the first report of IL-32 in 2005, there is increasing evidence that IL-32 plays an important role in the pathophysiology of both hematologic malignancies and solid tumors. Some IL-32 isoforms have been linked to disease outcome and were shown to positively influence tumor development and progression in various different malignancies, including gastric, breast and lung cancers. However, there are other reports suggesting a tumor suppressive role for some of IL-32 as well. For example, IL-32γ and IL-32β expression is associated with increased cancer cell death in colon cancer and melanoma, whereas expression of these isoforms is associated with increased invasion and migration in breast cancer cells. Furthermore, IL-32 isoforms α, β and γ also play an important role in regulating the anti-tumor immune response, thus also influencing tumor progression. In this review, we provide an overview of the role of IL-32 and its different isoforms in carcinogenesis, invasion and metastasis, angiogenesis and regulation of the anti-tumor immune response.
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30
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Dos Santos JC, Damen MSMA, Joosten LAB, Ribeiro-Dias F. Interleukin-32: An endogenous danger signal or master regulator of intracellular pathogen infections-Focus on leishmaniases. Semin Immunol 2018; 38:15-23. [PMID: 29551246 DOI: 10.1016/j.smim.2018.02.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Accepted: 02/23/2018] [Indexed: 02/07/2023]
Abstract
Interleukin 32 (IL-32) is an intracellular cytokine produced by immune and non immune cells after different stimuli. It contributes to inflammation and control of intracellular pathogens mainly by inducing proinflammatory cytokines and microbicidal molecules. Evidence is rising showing that IL-32 can be considered an endogenous danger signal after tissue injury, amplifying the inflammatory process and acquired immune responses. It seems to be a master regulator of intracellular infectious diseases. In this review, first the general properties of IL-32 are described followed by its role in the immunopathogenesis of inflammatory and infectious diseases. Roles of IL-32 in the control of infectious diseases caused by intracellular pathogens are reported, and later a focus on IL-32 in leishmaniases, diseases caused by an intracellular protozoan, is presented.
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Affiliation(s)
- Jéssica C Dos Santos
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands; Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Michelle S M A Damen
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Leo A B Joosten
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands; Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Fátima Ribeiro-Dias
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brazil.
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31
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Lee J, Kim KE, Cheon S, Song JH, Houh Y, Kim TS, Gil M, Lee KJ, Kim S, Kim D, Hur DY, Yang Y, Bang SI, Park HJ, Cho D. Interleukin-32α induces migration of human melanoma cells through downregulation of E-cadherin. Oncotarget 2018; 7:65825-65836. [PMID: 27589563 PMCID: PMC5323195 DOI: 10.18632/oncotarget.11669] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Accepted: 08/20/2016] [Indexed: 01/11/2023] Open
Abstract
Interleukin (IL)-32α, the shortest isoform of proinflammatory cytokine IL-32, is associated with various inflammatory diseases and cancers. However, its involvement in human melanoma is not understood. To determine the effect of IL-32α in melanoma, IL-32α levels were examined in human melanoma cell lines that exhibit different migratory abilities. IL-32α levels were higher in human melanoma cell lines with more migratory ability. An IL-32α-overexpressing G361 human melanoma cell line was generated to investigate the effect of IL-32α on melanoma migration. IL-32α-overexpressing G361 cells (G361-IL-32α) exhibit an increased migratory ability compared to vector control cells (G361-vector). To identify factors involved in IL-32α-induced migration, we compared expression of E-cadherin in G361-vector and G361-IL-32α cells. We observed decreased levels of E-cadherin in G361-IL-32α cells, resulting in F-actin polymerization. To further investigate signaling pathways related to IL-32α-induced migration, we treated G361-vector and G361-IL-32α cells with PD98059, a selective MEK inhibitor. Inhibition of Erk1/2 by PD98059 restored E-cadherin expression and decreased IL-32α-induced migration. In addition, cell invasiveness of G361-IL-32α cells was tested using an in vivo lung metastasis model. As results, lung metastasis was significantly increased by IL-32α overexpression. Taken together, these data indicate that IL-32α induced human melanoma migration via Erk1/2 activation, which repressed E-cadherin expression. Our findings suggest that IL-32α is a novel regulator of migration in melanoma.
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Affiliation(s)
- Joohyun Lee
- Department of Life Systems, Sookmyung Women's University, Yongsan-ku, Seoul 140-742, Republic of Korea
| | - Kyung Eun Kim
- Department of Cosmetic Sciences, Sookmyung Women's University, Yongsan-ku, Seoul 140-742, Republic of Korea
| | - Soyoung Cheon
- Department of Life Systems, Sookmyung Women's University, Yongsan-ku, Seoul 140-742, Republic of Korea
| | - Ju Han Song
- Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Younkyung Houh
- Department of Life Systems, Sookmyung Women's University, Yongsan-ku, Seoul 140-742, Republic of Korea
| | - Tae Sung Kim
- Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Minchan Gil
- Department of Cosmetic Sciences, Sookmyung Women's University, Yongsan-ku, Seoul 140-742, Republic of Korea
| | - Kyung Jin Lee
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
| | - Seonghan Kim
- Department of Anatomy, Inje University College of Medicine, Busan, 614-735, Republic of Korea
| | - Daejin Kim
- Department of Anatomy, Inje University College of Medicine, Busan, 614-735, Republic of Korea
| | - Dae Young Hur
- Department of Anatomy, Inje University College of Medicine, Busan, 614-735, Republic of Korea
| | - Yoolhee Yang
- Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 135-710, Republic of Korea
| | - Sa Ik Bang
- Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 135-710, Republic of Korea
| | - Hyun Jeong Park
- Department of Dermatology, Yeouido St. Mary's Hospital, The Catholic University of Korea, Seoul 150-713, Republic of Korea
| | - Daeho Cho
- Department of Life Systems, Sookmyung Women's University, Yongsan-ku, Seoul 140-742, Republic of Korea.,Department of Cosmetic Sciences, Sookmyung Women's University, Yongsan-ku, Seoul 140-742, Republic of Korea
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32
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Arts RJW, Joosten LAB, Netea MG. The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders. Front Immunol 2018. [PMID: 29515591 PMCID: PMC5826224 DOI: 10.3389/fimmu.2018.00298] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
During induction of trained immunity, monocytes and macrophages undergo a functional and transcriptional reprogramming toward increased activation. Important rewiring of cellular metabolism of the myeloid cells takes place during induction of trained immunity, including a shift toward glycolysis induced through the mTOR pathway, as well as glutaminolysis and cholesterol synthesis. Subsequently, this leads to modulation of the function of epigenetic enzymes, resulting in important changes in chromatin architecture that enables increased gene transcription. However, in addition to the beneficial effects of trained immunity as a host defense mechanism, we hypothesize that trained immunity also plays a deleterious role in the induction and/or maintenance of autoimmune and autoinflammatory diseases if inappropriately activated.
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Affiliation(s)
- Rob J W Arts
- Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
| | - Leo A B Joosten
- Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.,Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Mihai G Netea
- Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.,Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
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Alunno A, Carubbi F, Giacomelli R, Gerli R. Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets. BMC Rheumatol 2017; 1:3. [PMID: 30886947 PMCID: PMC6383595 DOI: 10.1186/s41927-017-0001-8] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 10/19/2017] [Indexed: 12/28/2022] Open
Abstract
In recent years, the landscape of pro- and anti-inflammatory cytokines has rapidly expanded with the identification of new members proven to be involved at different extent in the pathogenesis of chronic immune mediated inflammatory diseases including rheumatoid arthritis (RA). The advance of our understanding of mediators involved in the pathogenesis of RA and in consequence, the development of novel targeted therapies is necessary to provide patients not responding to currently available strategies with novel compounds. The aim of this review article is to provide an overview on recently identified cytokines, emphasizing their pathogenic role and therapeutic potential in RA. A systematic literature review was performed to retrieve articles related to every cytokine discussed in the review. In some cases, evidence from animal models and RA patients is already consistent to move forward into drug development. In others, conflicting observation and the paucity of data require further investigations.Forty years after the discovery of IL-1, the landscape of cytokines is continuously expanding with increasing possibilities to develop novel therapeutic strategies in RA.
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Affiliation(s)
- Alessia Alunno
- 1Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy
| | - Francesco Carubbi
- 2Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.,ASL1 Avezzano-L'Aquila-Sulmona, Department of Medicine, L'Aquila, Italy
| | - Roberto Giacomelli
- 2Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Roberto Gerli
- 1Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy
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Interleukin-32α promotes the proliferation of multiple myeloma cells by inducing production of IL-6 in bone marrow stromal cells. Oncotarget 2017; 8:92841-92854. [PMID: 29190960 PMCID: PMC5696226 DOI: 10.18632/oncotarget.21611] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 08/17/2017] [Indexed: 12/13/2022] Open
Abstract
Multiple myeloma (MM) is a malignant plasma disease closely associated with inflammation. In MM bone marrow microenvironment, bone marrow stromal cells (BMSCs) are the primary source of interleukin-6 (IL-6) secretion, which promotes the proliferation and progression of MM cells. However, it is still unknown how the microenvironment stimulates BMSCs to secrete IL-6. Interleukin-32 (IL-32) is a newly identified pro-inflammatory factor. It was reported that in solid tumors, IL-32 induces changes in other inflammatory factors including IL-6, IL-10, and TNF-α. The aim of this study was to investigate the expression of IL-32 and the role of IL-32 in the MM bone marrow microenvironment. Our data illustrate that MM patients have higher expression of IL-32 than healthy individuals in both bone marrow and peripheral blood. We used ELISA and qRT-PCR to find that malignant plasma cells are the primary source of IL-32 production in MM bone marrow. ELISA and Western blot analysis revealed that recombinant IL-32α induces production of IL-6 in BMSCs by activating NF-κB and STAT3 signaling pathways, konckdown of IL-32 receptor PR3 inhibit this process. Knockdown of IL-32 by shRNA decreased the proliferation in MM cells that induced by BMSCs. In conclusion, IL-32 secreted from MM cells has paracrine effect to induce production of IL-6 in BMSCs, thus feedback to promote MM cells growth.
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35
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Thomi R, Yerly D, Yawalkar N, Simon D, Schlapbach C, Hunger RE. Interleukin-32 is highly expressed in lesions of hidradenitis suppurativa. Br J Dermatol 2017; 177:1358-1366. [PMID: 28301691 DOI: 10.1111/bjd.15458] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/06/2017] [Indexed: 12/30/2022]
Abstract
BACKGROUND Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. Its immunopathogenic mechanisms are still poorly understood. Previous studies demonstrated that the proinflammatory cytokine interleukin (IL)-32 is implicated in the pathogenesis of other inflammatory diseases. OBJECTIVES To investigate the tissue expression and systemic levels of IL-32, as well as its cellular sources, in patients with HS in comparison with healthy donors and patients with two other inflammatory skin diseases: psoriasis and atopic dermatitis (AD). METHODS Tissue samples were obtained from healthy skin and lesional HS, psoriatic and AD skin to analyse the expression of IL-32 by immunohistochemistry and semiquantitative real-time polymerase chain reaction. The cellular source of the cytokine was determined by double immunofluorescence staining. Serum from the four donor groups was used to measure systemic levels of IL-32 by enzyme-linked immunosorbent assay. RESULTS IL-32 was upregulated in patients with HS in both lesional skin and serum when compared with healthy donors and patients with AD or psoriasis. In HS, IL-32 was found to be expressed by natural killer cells, T cells, macrophages and dendritic cells in highly infiltrated areas of the dermis. High IL32 mRNA levels in lesional HS skin coincided with high amounts of T cells and macrophages. Additionally, IL32 mRNA levels in lesional HS skin correlate positively with interferon-γ and IL-17A and negatively with IL-13. CONCLUSIONS Our findings suggest that IL-32 is overexpressed in HS. Targeting IL-32 may therefore represent a new therapeutic option for the treatment of this recalcitrant disease.
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Affiliation(s)
- R Thomi
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland
| | - D Yerly
- Department of Rheumatology, Immunology and Allergology, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland
| | - N Yawalkar
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland
| | - D Simon
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland
| | - C Schlapbach
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland
| | - R E Hunger
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland
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Damen MS, Popa CD, Netea MG, Dinarello CA, Joosten LA. Interleukin-32 in chronic inflammatory conditions is associated with a higher risk of cardiovascular diseases. Atherosclerosis 2017; 264:83-91. [DOI: 10.1016/j.atherosclerosis.2017.07.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 06/09/2017] [Accepted: 07/05/2017] [Indexed: 01/03/2023]
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Ha YJ, Park JS, Kang MI, Lee SK, Park YB, Lee SW. Increased serum interleukin-32 levels in patients with Behçet's disease. Int J Rheum Dis 2017; 21:2167-2174. [DOI: 10.1111/1756-185x.13072] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- You-Jung Ha
- Division of Rheumatology; Department of Internal Medicine; Seoul National University Bundang Hospital; Seongnam-si South Korea
| | - Jin-Su Park
- Division of Rheumatology; Department of Internal Medicine; National Health Insurance Service Ilsan Hospital; Goyang-si South Korea
| | - Mi-il Kang
- Division of Rheumatology; Department of Internal Medicine; Dankook University College of Medicine; Cheonan South Korea
| | - Soo-Kon Lee
- Division of Rheumatology; Department of Internal Medicine; Yonsei University College of Medicine; Seoul South Korea
| | - Yong-Beom Park
- Division of Rheumatology; Department of Internal Medicine; Yonsei University College of Medicine; Seoul South Korea
| | - Sang-Won Lee
- Division of Rheumatology; Department of Internal Medicine; Yonsei University College of Medicine; Seoul South Korea
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dos Santos JC, Heinhuis B, Gomes RS, Damen MSMA, Real F, Mortara RA, Keating ST, Dinarello CA, Joosten LAB, Ribeiro-Dias F. Cytokines and microbicidal molecules regulated by IL-32 in THP-1-derived human macrophages infected with New World Leishmania species. PLoS Negl Trop Dis 2017; 11:e0005413. [PMID: 28241012 PMCID: PMC5344527 DOI: 10.1371/journal.pntd.0005413] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 03/09/2017] [Accepted: 02/15/2017] [Indexed: 01/08/2023] Open
Abstract
Background Interleukin-32 (IL-32) is expressed in lesions of patients with American Tegumentary Leishmaniasis (ATL), but its precise role in the disease remains unknown. Methodology/Principal findings In the present study, silencing and overexpression of IL-32 was performed in THP-1-derived macrophages infected with Leishmania (Viannia) braziliensis or L. (Leishmania) amazonensis to investigate the role of IL-32 in infection. We report that Leishmania species induces IL-32γ, and show that intracellular IL-32γ protein production is dependent on endogenous TNFα. Silencing or overexpression of IL-32 demonstrated that this cytokine is closely related to TNFα and IL-8. Remarkably, the infection index was augmented in the absence of IL-32 and decreased in cells overexpressing this cytokine. Mechanistically, these effects can be explained by nitric oxide cathelicidin and β-defensin 2 production regulated by IL-32. Conclusions Thus, endogenous IL-32 is a crucial cytokine involved in the host defense against Leishmania parasites. Leishmania (V.) braziliensis and L. (L.) amazonensis are protozoa that infect macrophages and cause cutaneous and mucosal leishmaniasis. Here we showed that both Leishmania species induce the production of IL-32γ in human macrophages. This intracellular and pro-inflammatory cytokine mediates the production of cytokines, especially TNFα and IL-8, in Leishmania-infected macrophages. Differential effects of IL-32γ on TNFα, IL-10 and IL-1Ra production after infection with distinct Leishmania species were detected, consistent with the concept that IL-32γ can differently influence the outcome of inflammatory process in leishmaniasis lesions. Moreover, IL-32γ upregulates microbicidal molecules, antimicrobial peptides, as well as NO, which are known as important factors in parasite control. These results underscore IL-32γ as a crucial cytokine to host defense against leishmaniasis.
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Affiliation(s)
- Jéssica Cristina dos Santos
- Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Brazil
| | - Bas Heinhuis
- Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Rodrigo Saar Gomes
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Brazil
| | - Michelle S. M. A. Damen
- Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Fernando Real
- Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil
| | - Renato A. Mortara
- Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil
| | - Samuel T. Keating
- Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Charles A. Dinarello
- Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
- School of Medicine, Division of infectious diseases, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Leo A. B. Joosten
- Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Fátima Ribeiro-Dias
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Brazil
- * E-mail:
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Abstract
Interleukin-32 (IL-32) is a novel cytokine involved in inflammation and cancer development. IL-32 gene consists of eight small exons, and IL-32 mRNA has nine alternative spliced isoforms, and was thought to be secreted because it contains an internal signal sequence and lacks a transmembrane region. IL-32 is initially expressed selectively in activated T cells by mitogen and activated NK cells and their expression is strongly augmented by microbes, mitogens, and other cytokines. The IL-32 is induced mainly by pathogens and pro-inflammatory cytokines, but IL-32 is more prominent in immune cells than in non-immune tissues. The IL-32 transcript is expressed in various human tissues and organs such as the spleen, thymus, leukocyte, lung, small intestine, colon, prostate, heart, placenta, liver, muscle, kidney, pancreas, and brain. Cytokines are critical components of cell signaling pathways that are involved in the regulation of cell growth, metabolism, hormone signaling, immune regulation and a variety of other physiological functions. Earlier studies have demonstrated that IL-32 regulates cell growth, metabolism and immune regulation and is therefore involved in the pathologic regulator or protectant of inflammatory diseases. Previous studies defined that IL-32 is upregulated in the patients with several inflammatory diseases, and is induced by inflammatory responses. However, several reports suggested that IL-32 is downregulated in several inflammatory diseases including asthma, HIV infection disease, neuronal diseases, metabolic disorders, experimental colitis and metabolic disorders. IL-32 is also involved in various cancer malignancies including renal cancer, esophageal cancer and hepatocellular carcinoma, lung cancer, gastric cancer, breast cancer, pancreatic cancer, lymphoma, osteosarcoma, breast cancer, colon cancer and thyroid carcinoma. Other studies suggested that IL-32 decreases tumor development including cervical cancer, colon cancer and prostate cancer, melanoma, pancreatic cancer, liver cancer and chronic myeloid leukemia. Nevertheless, review articles that discuss the roles and its mechanism of IL-32 isoforms focusing on the therapeutic approaches have not yet been reported. In this review article, we will discuss recent findings regarding IL-32 in the development of diseases and further discuss therapeutic approaches targeting IL-32. Moreover, we will suggest that IL-32 could be the target of several diseases and the therapeutic agents for targeting IL-32 may have potential beneficial effects for the treatment of inflammatory diseases and cancers. Future research should open new avenues for the design of novel therapeutic approaches targeting IL-32.
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Affiliation(s)
- Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 361-951, Republic of Korea
| | - Dong Ju Son
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 361-951, Republic of Korea
| | - Chong Kil Lee
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 361-951, Republic of Korea
| | - Do-Young Yoon
- Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea
| | - Dong Hun Lee
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 361-951, Republic of Korea; Department of Pediatrics, Children's Heart Research and Outcomes (HeRO) Center, Emory University School of Medicine, 2015 Uppergate Drive, Lab 260, Atlanta, GA, 30322, United States
| | - Mi Hee Park
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 361-951, Republic of Korea.
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Damen MSMA, Agca R, Holewijn S, de Graaf J, Dos Santos JC, van Riel PL, Fransen J, Coenen MJH, Nurmohamed MT, Netea MG, Dinarello CA, Joosten LAB, Heinhuis B, Popa CD. IL-32 promoter SNP rs4786370 predisposes to modified lipoprotein profiles in patients with rheumatoid arthritis. Sci Rep 2017; 7:41629. [PMID: 28134327 PMCID: PMC5278556 DOI: 10.1038/srep41629] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 12/22/2016] [Indexed: 01/22/2023] Open
Abstract
Patients with rheumatoid arthritis (RA) are at higher risk of developing cardiovascular diseases (CVD). Interleukin (IL)-32 has previously been shown to be involved in the pathogenesis of RA and might be linked to the development of atherosclerosis. However, the exact mechanism linking IL-32 to CVD still needs to be elucidated. The influence of a functional genetic variant of IL-32 on lipid profiles and CVD risk was therefore studied in whole blood from individuals from the NBS cohort and RA patients from 2 independent cohorts. Lipid profiles were matched to the specific IL-32 genotypes. Allelic distribution was similar in all three groups. Interestingly, significantly higher levels of high density lipoprotein cholesterol (HDLc) were observed in individuals from the NBS cohort and RA patients from the Nijmegen cohort homozygous for the C allele (p = 0.0141 and p = 0.0314 respectively). In contrast, the CC-genotype was associated with elevated low density lipoprotein cholesterol (LDLc) and total cholesterol (TC) in individuals at higher risk for CVD (plaque positive) (p = 0.0396; p = 0.0363 respectively). Our study shows a functional effect of a promoter single-nucleotide polymorphism (SNP) in IL32 on lipid profiles in RA patients and individuals, suggesting a possible protective role of this SNP against CVD.
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Affiliation(s)
- Michelle S M A Damen
- Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Rabia Agca
- Amsterdam Rheumatology immunology Center, Department of Rheumatology, location CU University Medical Center and Reade, Amsterdam, The Netherlands
| | | | - Jacqueline de Graaf
- Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Jéssica C Dos Santos
- Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.,Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Brazil
| | - Piet L van Riel
- Department of Rheumatology, Bernhoven Ziekenhuis, Uden, The Netherlands
| | - Jaap Fransen
- Department of Rheumatology, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands
| | - Marieke J H Coenen
- Radboud Institute for Health Sciences, Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands
| | - Mike T Nurmohamed
- Amsterdam Rheumatology immunology Center, Department of Rheumatology, location CU University Medical Center and Reade, Amsterdam, The Netherlands
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Charles A Dinarello
- Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.,School of Medicine, Division of infectious diseases, University of Colorado Denver, Aurora, Colorado 80045, United States of America
| | - Leo A B Joosten
- Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Bas Heinhuis
- Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Calin D Popa
- Department of Rheumatology, Bernhoven Ziekenhuis, Uden, The Netherlands.,Department of Rheumatology, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands
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Lopes MR, Pereira JKN, de Melo Campos P, Machado-Neto JA, Traina F, Saad STO, Favaro P. De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes. Sci Rep 2017; 7:40707. [PMID: 28084439 PMCID: PMC5234038 DOI: 10.1038/srep40707] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 12/09/2016] [Indexed: 12/11/2022] Open
Abstract
The interaction between the bone marrow microenvironment and malignant hematopoietic cells can result in the protection of leukemia cells from chemotherapy in both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We, herein, characterized the changes in cytokine expression and the function of mesenchymal stromal cells (MSC) in patients with MDS, AML with myelodysplasia-related changes (MRC), a well-recognized clinical subtype of secondary AML, and de novo AML. We observed a significant inhibitory effect of MDS-MSC on T lymphocyte proliferation and no significant differences in any of the cytokines tested. AML-MSC inhibited T-cell proliferation only at a very low MSC/T cell ratio. When compared to the control, AML-MRCderived MSC presented a significant increase in IL6 expression, whereas de novo AML MSC presented a significant increase in the expression levels of VEGFA, CXCL12, RPGE2, IDO, IL1β, IL6 and IL32, followed by a decrease in IL10 expression. Furthermore, data indicate that IL-32 regulates stromal cell proliferation, has a chemotactic potential and participates in stromal cell crosstalk with leukemia cells, which could result in chemoresistance. Our results suggest that the differences between AML-MRC and de novo AML also extend into the leukemic stem cell niche and that IL-32 can participate in the regulation of the bone marrow cytokine milieu.
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Affiliation(s)
- Matheus Rodrigues Lopes
- Hematology and Transfusion Medicine Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil
| | - João Kleber Novais Pereira
- Hematology and Transfusion Medicine Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil
| | - Paula de Melo Campos
- Hematology and Transfusion Medicine Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil
| | - João Agostinho Machado-Neto
- Hematology and Transfusion Medicine Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil
| | - Fabiola Traina
- Hematology and Transfusion Medicine Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.,Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil
| | - Sara T Olalla Saad
- Hematology and Transfusion Medicine Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil
| | - Patricia Favaro
- Hematology and Transfusion Medicine Center - University of Campinas/Hemocentro - Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.,Department of Biological Sciences, Federal University of São Paulo, Diadema, São Paulo, Brazil
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Catalán V, Gómez-Ambrosi J, Rodríguez A, Ramírez B, Valentí V, Moncada R, Landecho MF, Silva C, Salvador J, Frühbeck G. Increased Interleukin-32 Levels in Obesity Promote Adipose Tissue Inflammation and Extracellular Matrix Remodeling: Effect of Weight Loss. Diabetes 2016; 65:3636-3648. [PMID: 27630206 DOI: 10.2337/db16-0287] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 09/04/2016] [Indexed: 12/28/2022]
Abstract
Interleukin (IL)-32 is a recently described cytokine involved in the regulation of inflammation. We aimed to explore whether IL-32 could function as an inflammatory and angiogenic factor in human obesity and obesity-associated type 2 diabetes. Samples obtained from 90 subjects were used in the study. Obese patients exhibited higher expression levels of IL-32 in visceral adipose tissue (AT) as well as in subcutaneous AT and peripheral blood mononuclear cells. IL32 was mainly expressed by stromovascular fraction cells, and its expression was significantly enhanced by inflammatory stimuli and hypoxia, whereas no changes were found after the incubation with anti-inflammatory cytokines. The addition of exogenous IL-32 induced the expression of inflammation and extracellular matrix-related genes in human adipocyte cultures, and IL32-silenced adipocytes showed a downregulation of inflammatory genes. Furthermore, adipocyte-conditioned media obtained from obese patients increased IL32 gene expression in human monocyte cultures, whereas the adipocyte-conditioned media from lean volunteers had no effect on IL32 mRNA levels. These findings provide evidence, for the first time, about the inflammatory and remodeling properties of IL-32 in AT, implicating this cytokine in obesity-associated comorbidities.
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Affiliation(s)
- Victoria Catalán
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red, Fisiopatología de la Obesidad y Nutrición, CIBEROBN, Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
| | - Javier Gómez-Ambrosi
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red, Fisiopatología de la Obesidad y Nutrición, CIBEROBN, Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
| | - Amaia Rodríguez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red, Fisiopatología de la Obesidad y Nutrición, CIBEROBN, Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
| | - Beatriz Ramírez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red, Fisiopatología de la Obesidad y Nutrición, CIBEROBN, Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
| | - Víctor Valentí
- Centro de Investigación Biomédica en Red, Fisiopatología de la Obesidad y Nutrición, CIBEROBN, Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain
| | - Rafael Moncada
- Centro de Investigación Biomédica en Red, Fisiopatología de la Obesidad y Nutrición, CIBEROBN, Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
- Department of Anesthesia, Clínica Universidad de Navarra, Pamplona, Spain
| | - Manuel F Landecho
- Department of Internal Medicine, Clínica Universidad de Navarra, Pamplona, Spain
- TRUEHF Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Camilo Silva
- Centro de Investigación Biomédica en Red, Fisiopatología de la Obesidad y Nutrición, CIBEROBN, Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Javier Salvador
- Centro de Investigación Biomédica en Red, Fisiopatología de la Obesidad y Nutrición, CIBEROBN, Instituto de Salud Carlos III, Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Gema Frühbeck
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red, Fisiopatología de la Obesidad y Nutrición, CIBEROBN, Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
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Park MH, Yoon DY, Ban JO, Kim DH, Lee DH, Song S, Kim Y, Han SB, Lee HP, Hong JT. Decreased severity of collagen antibody and lipopolysaccharide-induced arthritis in human IL-32β overexpressed transgenic mice. Oncotarget 2016; 6:38566-77. [PMID: 26497686 PMCID: PMC4770721 DOI: 10.18632/oncotarget.6160] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 10/01/2015] [Indexed: 12/19/2022] Open
Abstract
Interleukin (IL)-32, mainly produced by T-lymphocytes, natural killer cells, epithelial cells, and blood monocytes, is dominantly known as a pro-inflammatory cytokine. However, the role of IL-32 on inflammatory disease has been doubtful according to diverse conflicting results. This study was designed to examine the role of IL-32β on the development of collagen antibody (CAIA) and lipopolysaccharide (LPS)-induced inflammatory arthritis. Our data showed that the paw swelling volume and clinical score were significantly reduced in the CAIA and LPS-treated IL-32β transgenic mice compared with non-transgenic mice. The populations of cytotoxic T, NK and dendritic cells was inhibited and NF-κB and STAT3 activities were significantly lowered in the CAIA and LPS-treated IL-32β transgenic mice. The expression of pro-inflammatory proteins was prevented in the paw tissues of CAIA and LPS-treated IL-32β transgenic mice. In addition, IL-32β altered several cytokine levels in the blood, spleen and paw joint. Our data indicates that IL-32β comprehensively inhibits the inflammation responses in the CAIA and LPS-induced inflammatory arthritis model.
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Affiliation(s)
- Mi Hee Park
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Cheong-ju, Chungbuk, Republic of Korea
| | - Do-Young Yoon
- Department of Bioscience and Biotechnology, Laboratory of Cell Biology and Immunobiochemistry, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong 1, Gwangjin-gu, Seoul, Republic of Korea
| | - Jung Ok Ban
- Osong Medical Innovation Foundation, Osongsaengmyeong 1-ro, Osong-eup, Cheongwon-gun, Chungbuk, Republic of Korea
| | - Dae Hwan Kim
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Cheong-ju, Chungbuk, Republic of Korea
| | - Dong Hun Lee
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Cheong-ju, Chungbuk, Republic of Korea
| | - Sukgil Song
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Cheong-ju, Chungbuk, Republic of Korea
| | - Youngsoo Kim
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Cheong-ju, Chungbuk, Republic of Korea
| | - Sang-Bae Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Cheong-ju, Chungbuk, Republic of Korea
| | - Hee Pom Lee
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Cheong-ju, Chungbuk, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Cheong-ju, Chungbuk, Republic of Korea
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Sulforaphane regulates phenotypic and functional switching of both induced and spontaneously differentiating human monocytes. Int Immunopharmacol 2016; 35:85-98. [DOI: 10.1016/j.intimp.2016.03.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 03/05/2016] [Accepted: 03/08/2016] [Indexed: 12/26/2022]
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Cho JS, Kim JA, Park JH, Park IH, Han IH, Lee HM. Toll-like receptor 4-mediated expression of interleukin-32 via the c-Jun N-terminal kinase/protein kinase B/cyclic adenosine monophosphate response element binding protein pathway in chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol 2016; 6:1020-1028. [PMID: 27173130 DOI: 10.1002/alr.21792] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Revised: 03/14/2016] [Accepted: 03/25/2016] [Indexed: 01/22/2023]
Abstract
BACKGROUND Chronic rhinosinusitis with nasal polyps (CRSwNP) is prolonged inflammation of the sinonasal mucosa. Interleukin-32 (IL-32) is involved in the pathogenesis of chronic lung inflammatory diseases. The aim of study is to compare the expression level of IL-32 in normal nasal mucosa and CRSwNP and to investigate the mechanism underlying IL-32 expression in CRSwNP. METHODS IL-32 expression in nasal tissues, normal nasal mucosa-derived fibroblasts (NorDFs) and nasal polyp-derived fibroblasts (NPDFs), ex vivo explants of nasal tissues was measured by reverse-transcription polymerase chain reaction (RT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). NorDFs and NPDFs were exposed to lipopolysaccharide (LPS) and the expression level of IL-32 was measured. LPS from Rhodobactersphaeroides (RS) and small interference RNA against Toll-like receptor 4 (siTLR4) were used to inhibit signaling by TLR4. Activation of mitogen-activated protein kinase (MAPKs) (extracellular related kinase [ERK], p38, and c-Jun N-terminal kinase [JNK]), protein kinase B (AKT), and cyclic adenosine monophosphate response element binding protein (CREB) was examined using western blot analysis. RESULTS Expression of IL-32 was increased in CRSwNP compared to normal nasal mucosa. LPS induced expression of IL-32 in a time-dependent manner. The induction of IL-32 expression in NPDFS was more effective than in NorDFs. Treatment with RS and siTLR4 inhibited the messenger RNA (mRNA) expression of TLR4, myeloid differentiation primary response 88 (MyD88), and IL-32 in LPS-stimulated NPDFs. IL-32 expression was specifically activated by JNK, AKT, and CREB in LPS-stimulated NPDFs and CRSwNP ex vivo explants. CONCLUSION The sensitivity for IL-32 expression by LPS was increased in CRSwNP compared to normal nasal mucosa. LPS effectively induced IL-32 expression in NPDFs than in NorDFs through the TLR4-JNK-AKT-CREB signaling pathway. Therefore, IL-32 seems to be involved in the pathogenesis of CRSwNP.
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Affiliation(s)
- Jung-Sun Cho
- Biomedical Science, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, Korea.,Institute for Medical Devices Clinical Trial Center, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, South Korea
| | - Jin-Ah Kim
- Biomedical Science, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, Korea
| | - Joo-Hoo Park
- Biomedical Science, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, Korea
| | - Il-Ho Park
- Institute for Medical Devices Clinical Trial Center, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, South Korea.,Department of Otorhinolaryngology- Head and Neck Surgery, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, South Korea
| | - In-Hye Han
- Biomedical Science, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, Korea
| | - Heung-Man Lee
- Biomedical Science, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, Korea. .,Institute for Medical Devices Clinical Trial Center, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, South Korea. .,Department of Otorhinolaryngology- Head and Neck Surgery, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, South Korea. .,Research-Driven Hospital, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, South Korea.
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IL-32: A Novel Pluripotent Inflammatory Interleukin, towards Gastric Inflammation, Gastric Cancer, and Chronic Rhino Sinusitis. Mediators Inflamm 2016; 2016:8413768. [PMID: 27143819 PMCID: PMC4837279 DOI: 10.1155/2016/8413768] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Revised: 02/23/2016] [Accepted: 03/20/2016] [Indexed: 12/15/2022] Open
Abstract
A vast variety of nonstructural proteins have been studied for their key roles and involvement in a number of biological phenomenona. Interleukin-32 is a novel cytokine whose presence has been confirmed in most of the mammals except rodents. The IL-32 gene was identified on human chromosome 16 p13.3. The gene has eight exons and nine splice variants, namely, IL-32α, IL-32β, IL-32γ, IL-32δ, IL-32ε, IL-32ζ, IL-32η, IL-32θ, and IL-32s. It was found to induce the expression of various inflammatory cytokines including TNF-α, IL-6, and IL-1β as well as macrophage inflammatory protein-2 (MIP-2) and has been reported previously to be involved in the pathogenesis and progression of a number of inflammatory disorders, namely, inflammatory bowel disease (IBD), gastric inflammation and cancer, rheumatoid arthritis, and chronic obstructive pulmonary disease (COPD). In the current review, we have highlighted the involvement of IL-32 in gastric cancer, gastric inflammation, and chronic rhinosinusitis. We have also tried to explore various mechanisms suspected to induce the expression of this extraordinary cytokine as well as various mechanisms of action employed by IL-32 during the mediation and progression of the above said problems.
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Nicholl MB, Chen X, Qin C, Bai Q, Zhu Z, Davis MR, Fang Y. IL-32α has differential effects on proliferation and apoptosis of human melanoma cell lines. J Surg Oncol 2016; 113:364-9. [DOI: 10.1002/jso.24142] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 12/08/2015] [Indexed: 12/11/2022]
Affiliation(s)
- Michael B. Nicholl
- Ellis Fischel Cancer Center; University of Missouri School of Medicine; Columbia Missouri
- South Texas Veterans Health Care System; San Antonio Texas
| | - Xuhui Chen
- Ellis Fischel Cancer Center; University of Missouri School of Medicine; Columbia Missouri
- Luohu Hospital; Shenzhen China
| | - Chenglu Qin
- Ellis Fischel Cancer Center; University of Missouri School of Medicine; Columbia Missouri
- Luohu Hospital; Shenzhen China
| | - Qian Bai
- Ellis Fischel Cancer Center; University of Missouri School of Medicine; Columbia Missouri
| | - Ziwen Zhu
- Ellis Fischel Cancer Center; University of Missouri School of Medicine; Columbia Missouri
| | - Matthew R. Davis
- Ellis Fischel Cancer Center; University of Missouri School of Medicine; Columbia Missouri
| | - Yujiang Fang
- Ellis Fischel Cancer Center; University of Missouri School of Medicine; Columbia Missouri
- Des Moines University; Des Moines Iowa
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Heinhuis B, Plantinga TS, Semango G, Küsters B, Netea MG, Dinarello CA, Smit JW, Netea-Maier RT, Joosten LA. Alternatively spliced isoforms of IL-32 differentially influence cell death pathways in cancer cell lines. Carcinogenesis 2015; 37:197-205. [DOI: 10.1093/carcin/bgv172] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 12/02/2015] [Indexed: 12/14/2022] Open
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Huang F, Wachi S, Liu H, Jung SS, August A. IL-32B is the predominant isoform expressed under inflammatory conditions in vitro and in COPD. ACTA ACUST UNITED AC 2015. [DOI: 10.1186/s40749-015-0006-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Cai A, Qi S, Su Z, Shen H, Ma W, Dai Y. Tripterygium glycosides inhibit inflammatory mediators in the rat synovial RSC-364 cell line stimulated with interleukin-1β. Biomed Rep 2015; 3:763-766. [PMID: 26623013 DOI: 10.3892/br.2015.501] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 04/24/2015] [Indexed: 01/08/2023] Open
Abstract
Tripterygium glycosides (TG) are extracted from a traditional Chinese medicinal herb. Using the compound, progress has been made in the treatment of rheumatoid arthritis (RA), but the underlying mechanism of its action is poorly understood. The purpose of the present study was to investigate the role of TG in preventing inflammatory arthritis. An inflammatory cell model was established in the rat synovial RSC-364 cell line via induction with interleukin (IL)-1β. The expression of IL-32 and matrix metalloproteinases (MMP-1 and MMP-9) was determined using an enzyme-linked immunosorbent assay. Compared with the control group (without IL-1β), IL-1β in the treatment group induced the expression of IL-32, MMP-1 and MMP-9 in RSC-364 cells. When a different dose of TG was added to RSC-364 cells stimulated with IL-1β, TG decreased the expression levels of IL-32, MMP-1 and MMP-9 in a dose-dependent manner. These results indicated that TG suppressed the inflammation response in RSC-364 cells. Taken together, these findings may contribute to a better understanding of the role of TG in the anti-inflammatory therapeutics for RA.
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Affiliation(s)
- Anji Cai
- Department of Clinical Laboratory, Nanshan Affiliated Hospital of Guangdong Medical College, Shenzhen, Guangdong 518020, P.R. China
| | - Suwen Qi
- Department of Biomedical Engineering, Medical School, Shenzhen University, Shenzhen, Guangdong 518020, P.R. China
| | - Zhuowa Su
- Department of Clinical Laboratory, Nanshan Affiliated Hospital of Guangdong Medical College, Shenzhen, Guangdong 518020, P.R. China
| | - Huaqing Shen
- Department of Clinical Laboratory, Nanshan Affiliated Hospital of Guangdong Medical College, Shenzhen, Guangdong 518020, P.R. China
| | - Wengsong Ma
- Department of Clinical Laboratory, Nanshan Affiliated Hospital of Guangdong Medical College, Shenzhen, Guangdong 518020, P.R. China
| | - Yong Dai
- The Second Clinical Medical College, Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
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