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Yazdanpanah E, Pazoki A, Dadfar S, Nemati MH, Sajad Siadati SM, Tarahomi M, Orooji N, Haghmorad D, Oksenych V. Interleukin-27 and Autoimmune Disorders: A Compressive Review of Immunological Functions. Biomolecules 2024; 14:1489. [PMID: 39766196 PMCID: PMC11672993 DOI: 10.3390/biom14121489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 01/11/2025] Open
Abstract
Autoimmune disorders (ADs) pose significant health and economic burdens globally, characterized by the body's immune system mistakenly attacking its own tissues. While the precise mechanisms driving their development remain elusive, a combination of genetic predisposition(s) and environmental triggers is implicated. Interleukin-27 (IL-27), among numerous cytokines involved, has emerged as a key regulator, exhibiting dual roles in immune modulation. This review delves into the molecular structure and signaling mechanisms of IL-27, highlighting its diverse effects on various immune cells. Additionally, it explores the involvement of IL-27 in autoimmune diseases, such as multiple sclerosis (MS) and rheumatoid arthritis (RA), offering insights into its potential therapeutic implications. Moreover, its involvement in autoimmune diseases like type 1 diabetes (T1D), inflammatory bowel disease (IBD), myasthenia gravis (MG), Sjögren's syndrome (SS), and Guillain-Barré syndrome (GBS) is multifaceted, with potential diagnostic and therapeutic implications across these conditions. Further research is essential to fully understand IL-27's mechanisms of action and therapeutic potential in autoimmune diseases.
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Affiliation(s)
- Esmaeil Yazdanpanah
- Student Research Committee, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Alireza Pazoki
- Student Research Committee, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Sepehr Dadfar
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Mohammad Hosein Nemati
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | | | - Mahdieh Tarahomi
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Niloufar Orooji
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Dariush Haghmorad
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Valentyn Oksenych
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7028 Trondheim, Norway
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden
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Xue Y, Zhou Y, Li C, Zhang J, Liu F, Shi R. Causal relationship between Interleukin-27 expression levels and osteoporosis: a bidirectional mendelian randomization study. BMC Musculoskelet Disord 2024; 25:680. [PMID: 39210324 PMCID: PMC11363690 DOI: 10.1186/s12891-024-07765-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 08/08/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND This study aimed to evaluate the causal relationship between Interleukin-27 (IL-27) and osteoporosis by bidirectional Mendelian randomization (MR) analysis. METHODS Firstly, the genome-wide association study summary data of osteoporosis (finn-b-M13_OSTEOPOROSIS) and IL-27 levels (ebi-a-GCST90012017) were picked out from the Integrative Epidemiology Unit (IEU) OpenGWAS database. After filtrating instrumental variables (IVs), the bidirectional MR analysis between IL-27 levels and osteoporosis was performed by MR-Egger, Weighted median, Simple mode, Weighted mode, and Inverse variance weighted (IVW). Subsequently, the sensitivity analysis was adopted to evaluate the reliability of the MR results via the Heterogeneity, Horizontal pleiotropy test and Leave-One-Out (LOO) analysis. Finally, the enrichment analysis of genes corresponding to SNPs related to IL-27 levels derived from eQTLGen database was executed to explore in depth the biological function and regulatory mechanism of these genes on osteoporosis occurrence. RESULTS The bidirectional MR results based on IVW method revealed that IL-27 level as a risk factor was causally related to osteoporosis (P = 0.004, odds ratio (OR) = 1.123, 95% confidence interval (CI) = 1.037-1.217), whereas osteoporosis was not in significant connection with IL-27 levels (P > 0.05). In regard to the sensitivity analysis for forward MR results, there was no heterogeneity and horizontal pleiotropy, and no SNPs relevant to IL-27 levels existed severe bias, suggesting the reliability of forward MR analysis. Furthermore, a total of 74 genes corresponding to 26 SNPs of IL-27 levels were obtained and were mainly involved in immune and inflammatory pathways including MyD88-dependent toll-like receptor signaling pathway, Toll-like receptor signaling pathway, cytosolic DNA-sensing pathway and so forth. CONCLUSIONS This study supported that IL-27 level as a risk factor was causally connected with osteoporosis and might regulate the disease occurrence and progression by means of immune and inflammatory mechanisms, which could provide important reference and evidence for further exploring the role of IL-27 in the development of osteoporosis.
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Affiliation(s)
- Yun Xue
- Beijing Research Institute of Traumatology and Orthopaedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
| | - You Zhou
- Beijing Research Institute of Traumatology and Orthopaedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
| | - Chunyan Li
- Department of Laboratory Medicine, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
| | - Jingshuang Zhang
- Beijing Research Institute of Traumatology and Orthopaedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
| | - Fei Liu
- Beijing Research Institute of Traumatology and Orthopaedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
| | - Rui Shi
- Beijing Research Institute of Traumatology and Orthopaedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China.
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Xu WD, Wang DC, Zhao M, Huang AF. An updated advancement of bifunctional IL-27 in inflammatory autoimmune diseases. Front Immunol 2024; 15:1366377. [PMID: 38566992 PMCID: PMC10985211 DOI: 10.3389/fimmu.2024.1366377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 03/04/2024] [Indexed: 04/04/2024] Open
Abstract
Interleukin-27 (IL-27) is a member of the IL-12 family. The gene encoding IL-27 is located at chromosome 16p11. IL-27 is considered as a heterodimeric cytokine, which consists of Epstein-Barr virus (EBV)-induced gene 3 (Ebi3) and IL-27p28. Based on the function of IL-27, it binds to receptor IL-27rα or gp130 and then regulates downstream cascade. To date, findings show that the expression of IL-27 is abnormal in different inflammatory autoimmune diseases (including systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome, Behcet's disease, inflammatory bowel disease, multiple sclerosis, systemic sclerosis, type 1 diabetes, Vogt-Koyanagi-Harada, and ankylosing spondylitis). Moreover, in vivo and in vitro studies demonstrated that IL-27 is significantly in3volved in the development of these diseases by regulating innate and adaptive immune responses, playing either an anti-inflammatory or a pro-inflammatory role. In this review, we comprehensively summarized information about IL-27 and autoimmunity based on available evidence. It is hoped that targeting IL-27 will hold great promise in the treatment of inflammatory autoimmune disorders in the future.
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Affiliation(s)
- Wang-Dong Xu
- Department of Evidence-Based Medicine, School of Public Health, Southwest Medical University, Luzhou, Sichuan, China
| | - Da-Cheng Wang
- Department of Evidence-Based Medicine, School of Public Health, Southwest Medical University, Luzhou, Sichuan, China
| | - Ming Zhao
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, China
| | - An-Fang Huang
- Department of Rheumatology and Immunology, Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
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Xu J, Yu L, Liu F, Wan L, Deng Z. The effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review. Front Immunol 2023; 14:1222129. [PMID: 37475866 PMCID: PMC10355373 DOI: 10.3389/fimmu.2023.1222129] [Citation(s) in RCA: 65] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 06/12/2023] [Indexed: 07/22/2023] Open
Abstract
The complicated connections and cross talk between the skeletal system and the immune system are attracting more attention, which is developing into the field of Osteoimmunology. In this field, cytokines that are among osteoblasts and osteoclasts play a critical role in bone remodeling, which is a pathological process in the pathogenesis and development of osteoporosis. Those cytokines include the tumor necrosis factor (TNF) family, the interleukin (IL) family, interferon (IFN), chemokines, and so on, most of which influence the bone microenvironment, osteoblasts, and osteoclasts. This review summarizes the effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis, aiming to providing the latest reference to the role of immunology in osteoporosis.
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Affiliation(s)
- Jie Xu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Linxin Yu
- Renmin Hospital of Wuhan University, Wuhan, China
| | - Feng Liu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Longbiao Wan
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhenhua Deng
- Hubei Provincial Hospital of Traditional Chinese Medicine (TCM), Wuhan, China
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IL-27 regulates autophagy in rheumatoid arthritis fibroblast-like synoviocytes via STAT3 signaling. Immunobiology 2022; 227:152241. [PMID: 35820245 DOI: 10.1016/j.imbio.2022.152241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 06/19/2022] [Accepted: 07/02/2022] [Indexed: 02/06/2023]
Abstract
Rheumatoid arthritis (RA) is a highly prevalent autoimmune condition associated with pronounced synovial inflammation. The majority of RA patients required long-term treatment to control disease progression, thus imposing a significant financial burden on affected individuals. The development of RA is critically influenced by fibroblast-like synoviocytes (FLSs) within the synovial lining. IL-27 is an IL-6/IL-12 family cytokine that has recently been shown to play varied pro-inflammatory or protective roles in particular autoimmune diseases. However, the effects of IL-27 on FLSs in the context of RA have yet to be clarified and warrant further research. This study was developed to evaluate the impact of IL-27 treatment on apoptotic and autophagic activity in RA-associated FLSs, with a particular focus on the role of the STAT3 pathway in this regulatory context. Through these experiments, we found that IL-27 was able to suppress FLS proliferation and autophagic activity, with a high dose of this cytokine (100 ng/mL) markedly suppressing autophagy while simultaneously inducing some level of cellular apoptosis. The STAT3 inhibitor STA21 was found to reverse the IL-27-mediated suppression of autophagic activity in these RA-associated FLSs. Imbalanced cellular proliferation and apoptosis is of critical importance in the context of RA progression, and we found that IL-27 was able to regulate such imbalance and to enhance the apoptotic activity of RA FLSs by inhibiting rapamycin-activated autophagy. Together, these results indicate that IL-27 can regulate autophagic activity within RA-associated FLSs via the STAT3 signaling pathway, leading to inhibition of cellular proliferation.
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Li T, Hadigan C, Whitlock JM, Qin J, Kumar J, Kumar P, Catalfamo M. IL-27 Modulates the Cytokine Secretion in the T Cell-Osteoclast Crosstalk During HIV Infection. Front Immunol 2022; 13:818677. [PMID: 35479090 PMCID: PMC9037094 DOI: 10.3389/fimmu.2022.818677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 03/07/2022] [Indexed: 11/13/2022] Open
Abstract
In People with HIV (PWH), chronic immune activation and systemic inflammation are associated with increased risk to develop comorbidities including bone loss. Numerous cells of the immune system, namely, T cells are involved in the regulation of the bone homeostasis and osteoclasts (OCs) activity. IL-27, a cytokine that belongs to the IL-12 family can regulate the secretion of pro- and anti-inflammatory cytokines by T cells, however its role in the setting of HIV is largely unknown. In the present study, we determined the impact of OCs in T cell secretion of cytokines and whether IL-27 can regulate this function. We found that the presence of OCs in the T cell cultures significantly enhanced secretion of IFNγ, TNFα, IL-17, RANKL, and IL-10 in both PWH and healthy controls. In PWH, IL-27 inhibited IL-17 secretion and downregulated surface expression of RANKL in CD4 T cells. All together these results suggest that in the context of HIV infection IL-27 may favor IFNγ and TNFα secretion at the sites of bone remodeling.
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Affiliation(s)
- Tong Li
- Department of Microbiology and Immunology, Georgetown University School of Medicine, Washington, DC, United States
| | - Colleen Hadigan
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Jarred M. Whitlock
- Section on Membrane Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Jing Qin
- Biostatistics Research Branch, Division of Clinical Research (DCR), National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Jai Kumar
- Division of Infectious Diseases and Travel Medicine, Georgetown University School of Medicine, Washington, DC, United States
| | - Princy Kumar
- Division of Infectious Diseases and Travel Medicine, Georgetown University School of Medicine, Washington, DC, United States
| | - Marta Catalfamo
- Department of Microbiology and Immunology, Georgetown University School of Medicine, Washington, DC, United States
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Han L, Chen Z, Yu K, Yan J, Li T, Ba X, Lin W, Huang Y, Shen P, Huang Y, Qin K, Geng Y, Liu Y, Wang Y, Tu S. Interleukin 27 Signaling in Rheumatoid Arthritis Patients: Good or Evil? Front Immunol 2022; 12:787252. [PMID: 35058928 PMCID: PMC8764250 DOI: 10.3389/fimmu.2021.787252] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/06/2021] [Indexed: 12/12/2022] Open
Abstract
The occurrence and development of rheumatoid arthritis (RA) is regulated by numerous cytokines. Interleukin 27 (IL-27) is a soluble cytokine that exerts biological effects by regulating the Janus tyrosine kinase (JAK)/signal transducer and activator of the transcription (STAT) signaling pathway via the IL-27 receptor. IL-27 is known for its pleiotropic roles in modulating inflammatory responses. Previous studies found that IL-27 levels are elevated in RA blood, synovial fluid, and rheumatoid nodules. Cellular and animal experiments indicated that IL-27 exerts multiple regulatory functions in RA patients via different mechanisms. IL-27 inhibits ectopic-like structure (ELS) formation and CD4+ T helper type 2 (Th2) cell, CD4+ T helper type 17 (Th17) cell, and osteoclast differentiation in RA, contributing to alleviating RA. However, IL-27 promotes Th1 cell differentiation, which may exacerbate RA synovitis. Moreover, IL-27 also acts on RA synovial fibroblasts (RA-FLSs) and regulatory T cells (Tregs), but some of its functions are unclear. There is currently insufficient evidence to determine whether IL-27 promotes or relieves RA. Targeting IL-27 signaling in RA treatment should be deliberate based on current knowledge.
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Affiliation(s)
- Liang Han
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Zhe Chen
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Kun Yu
- Department of Cardiology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Jiahui Yan
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Tingting Li
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Xin Ba
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Weiji Lin
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Yao Huang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Pan Shen
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Ying Huang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Kai Qin
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Yinhong Geng
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yafei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yu Wang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Shenghao Tu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
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Influences of the IL-6 cytokine family on bone structure and function. Cytokine 2021; 146:155655. [PMID: 34332274 DOI: 10.1016/j.cyto.2021.155655] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/08/2021] [Accepted: 07/12/2021] [Indexed: 01/12/2023]
Abstract
The IL-6 family of cytokines comprises a large group of cytokines that all act via the formation of a signaling complex that includes the glycoprotein 130 (gp130) receptor. Despite this, many of these cytokines have unique roles that regulate the activity of bone forming osteoblasts, bone resorbing osteoclasts, bone-resident osteocytes, and cartilage cells (chondrocytes). These include specific functions in craniofacial development, longitudinal bone growth, and the maintenance of trabecular and cortical bone structure, and have been implicated in musculoskeletal pathologies such as craniosynostosis, osteoporosis, rheumatoid arthritis, osteoarthritis, and heterotopic ossifications. This review will work systematically through each member of this family and provide an overview and an update on the expression patterns and functions of each of these cytokines in the skeleton, as well as their negative feedback pathways, particularly suppressor of cytokine signaling 3 (SOCS3). The specific cytokines described are interleukin 6 (IL-6), interleukin 11 (IL-11), oncostatin M (OSM), leukemia inhibitory factor (LIF), cardiotrophin 1 (CT-1), ciliary neurotrophic factor (CNTF), cardiotrophin-like cytokine factor 1 (CLCF1), neuropoietin, humanin and interleukin 27 (IL-27).
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Cui Z, Feng R, Liu Z, Gong Y, Zhang Y. Receptor Activator of Nuclear Factor (Nf)-kb Ligand Promotes T Helper 17 Cell Differentiation through Fas. Immunol Invest 2021; 51:1385-1397. [PMID: 34238108 DOI: 10.1080/08820139.2021.1948050] [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] [Indexed: 12/12/2022]
Abstract
T helper 17 (Th17) cells play important role in the defense against pathogens and autoimmune diseases. Many cytokines can induce Th17 cell differentiation. However, the mechanism of Th17 cell differentiation is not well clarified. RankL, a member of the TNF superfamily, binds with Rank and then participates in the proliferation and differentiation of many kinds of cells. Recent studies showed that RankL-Rank signaling is closely related to Th17 differentiation and function. The detail of the Rank-RankL pathway in Th17 cell differentiation is still unclear. To illustrate the role of Rank-RankL in Th17 differentiation, naive CD4 + T cells were differentiated into Th17 cells with or without RankL stimulation. During Th17 differentiation, the expression of Rank obviously increased. The RankL stimulation significantly increased Th17 cell differentiation indicated by increased IL-17-positive cell number, highly expressed IL-17 and IL-22 and elevated IL-17 secretion. These effects were canceled by Rank-Fc addition. In further study, RankL treatment during Th17 differentiation up-regulated Fas expression. Fas knockdown inhibited the Th17 differentiation promoted by RankL. In this study, it was confirmed that Rank-RankL signaling could promote Th17 cell differentiation through Fas induction.
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Affiliation(s)
- Zilin Cui
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Rui Feng
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Zirong Liu
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Yehong Gong
- Department of General Surgery, Xincheng Hospital of Tianjin University, Tianjin, China
| | - Yamin Zhang
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
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Shahi A, Afzali S, Salehi S, Aslani S, Mahmoudi M, Jamshidi A, Amirzargar A. IL-27 and autoimmune rheumatologic diseases: The good, the bad, and the ugly. Int Immunopharmacol 2020; 84:106538. [PMID: 32361567 DOI: 10.1016/j.intimp.2020.106538] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 04/09/2020] [Accepted: 04/20/2020] [Indexed: 12/24/2022]
Abstract
The footprint of cytokines is evident in almost every biological process, such as development, as well as the pathogenesis of the different diseases, immune responses to pathogens, etc. These small proteins are categorized into different functional classes; for instance, they can play a pro-inflammatory or anti-inflammatory role in different situations, or they can confer a polarization to the immune system. Interleukin (IL)-27 is a member of the IL-12 family. Antigen-presenting cells are the primary source of IL-27 production, which exerts its effects by bindings to the IL-27 receptor expressed on the surface of target cells. Interaction of IL-27 and IL-27 receptor leads to activation of the JAK-STAT and p38 MAPK signaling pathways. Most studies focused on the inflammatory effects of this cytokine, but gradually anti-inflammatory effects were also revealed for this cytokine, which changed the traditional perception of the function of this cytokine. The functionality of IL-27 in the pathogenesis of rheumatic diseases has been attributed to a double-blade sword. Hence, novel therapeutic approaches have been devised targeting IL-12 family that has been accompanied with promising results. In this review, we focused on the inflammatory and anti-inflammatory properties of IL-27 in different autoimmune rheumatologic diseases and its plausible therapeutic potentials.
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Affiliation(s)
- Abbas Shahi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Shima Afzali
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeedeh Salehi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Aslani
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Ahmadreza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Aliakbar Amirzargar
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Abstract
Cytokines and hematopoietic growth factors have traditionally been thought of as regulators of the development and function of immune and blood cells. However, an ever-expanding number of these factors have been discovered to have major effects on bone cells and the development of the skeleton in health and disease (Table 1). In addition, several cytokines have been directly linked to the development of osteoporosis in both animal models and in patients. In order to understand the mechanisms regulating bone cells and how this may be dysregulated in disease states, it is necessary to appreciate the diverse effects that cytokines and inflammation have on osteoblasts, osteoclasts, and bone mass. This chapter provides a broad overview of this topic with extensive references so that, if desired, readers can access specific references to delve into individual topics in greater detail.
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Affiliation(s)
- Joseph Lorenzo
- Departments of Medicine and Orthopaedic Surgery, UConn Health, Farmington, CT, USA.
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Wu L, Su Y, Lin F, Zhu S, Wang J, Hou Y, Du J, Liu Y, Guo L. MicroRNA‐21 promotes orthodontic tooth movement by modulating the RANKL/OPG balance in T cells. Oral Dis 2019; 26:370-380. [DOI: 10.1111/odi.13239] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 10/29/2019] [Accepted: 11/10/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Lili Wu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University Beijing China
| | - Yingying Su
- Department of Stomatology Beijing Tiantan Hospital Capital Medical University Beijing China
| | - Feiran Lin
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University Beijing China
| | - Siying Zhu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University Beijing China
| | - Jingyi Wang
- School of Dental Medicine University of Pennsylvania Philadelphia PA USA
| | - Yanan Hou
- Department of Orthodontics School of Stomatology the Third Dental Center Peking University Beijing China
| | - Juan Du
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University Beijing China
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University Beijing China
| | - Lijia Guo
- Department of Orthodontics School of Stomatology Capital Medical University Beijing China
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Zhang T, Yao Y. Effects of inflammatory cytokines on bone/cartilage repair. J Cell Biochem 2019; 120:6841-6850. [PMID: 30335899 DOI: 10.1002/jcb.27953] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 10/02/2018] [Indexed: 01/24/2023]
Abstract
Many inflammatory factors can affect cell behaviors and work as a form of inter-regulatory networks through the inflammatory pathway. Inflammatory cytokines are critical for triggering bone regeneration after fracture or bone injury. Also, inflammatory cytokines play an important role in cartilage repair. The synergistic or antagonistic effects of both proinflammatory and anti-inflammatory cytokines have a great influence on fracture healing. This review discusses key inflammatory cytokines and signaling pathways involved in bone or cartilage repair.
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Affiliation(s)
- Tingshuai Zhang
- Department of Joint Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangdong Key Laboratory of Orthopaedic Technology And Implant Materials, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yongchang Yao
- Department of Joint Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangdong Key Laboratory of Orthopaedic Technology And Implant Materials, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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14
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Sharma J, Larkin J. Therapeutic Implication of SOCS1 Modulation in the Treatment of Autoimmunity and Cancer. Front Pharmacol 2019; 10:324. [PMID: 31105556 PMCID: PMC6499178 DOI: 10.3389/fphar.2019.00324] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 03/18/2019] [Indexed: 12/14/2022] Open
Abstract
The suppressor of cytokine signaling (SOCS) family of intracellular proteins has a vital role in the regulation of the immune system and resolution of inflammatory cascades. SOCS1, also called STAT-induced STAT inhibitor (SSI) or JAK-binding protein (JAB), is a member of the SOCS family with actions ranging from immune modulation to cell cycle regulation. Knockout of SOCS1 leads to perinatal lethality in mice and increased vulnerability to cancer, while several SNPs associated with the SOCS1 gene have been implicated in human inflammation-mediated diseases. In this review, we describe the mechanism of action of SOCS1 and its potential therapeutic role in the prevention and treatment of autoimmunity and cancer. We also provide a brief outline of the other JAK inhibitors, both FDA-approved and under investigation.
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Affiliation(s)
- Jatin Sharma
- Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL, United States
| | - Joseph Larkin
- Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL, United States
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15
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Jones GW, Hill DG, Cardus A, Jones SA. IL-27: a double agent in the IL-6 family. Clin Exp Immunol 2018; 193:37-46. [PMID: 29437229 DOI: 10.1111/cei.13116] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/02/2018] [Indexed: 12/31/2022] Open
Abstract
The cytokine interleukin (IL)-6 is a major therapeutic target for the treatment of various inflammatory and autoimmune diseases. While IL-6 receives considerable attention in studies of innate and adaptive immunity, the IL-6-related family member IL-27 is recognized increasingly for its effects on cellular proliferation, differentiation and leucocyte effector functions. Both cytokines activate responses in myeloid and stromal tissue cells, where they direct the transition from innate to adaptive immunity. However, they are identified frequently as lymphokines that control responses in T cells and B cells. In this regard, IL-27 often opposes the action of IL-6. Here, we will review the role of IL-6 and IL-27 in inflammation, with a particular focus on inflammatory arthritis, and discuss their importance in the diagnosis, stratification and treatment of autoimmune disease.
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Affiliation(s)
- G W Jones
- Division of Infection and Immunity, The School of Medicine, Systems Immunity University Research Institute, College of Biomedical and Life Sciences, Cardiff University, Cardiff, Wales, UK
| | - D G Hill
- Division of Infection and Immunity, The School of Medicine, Systems Immunity University Research Institute, College of Biomedical and Life Sciences, Cardiff University, Cardiff, Wales, UK
| | - A Cardus
- Division of Infection and Immunity, The School of Medicine, Systems Immunity University Research Institute, College of Biomedical and Life Sciences, Cardiff University, Cardiff, Wales, UK
| | - S A Jones
- Division of Infection and Immunity, The School of Medicine, Systems Immunity University Research Institute, College of Biomedical and Life Sciences, Cardiff University, Cardiff, Wales, UK
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16
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Amarasekara DS, Yun H, Kim S, Lee N, Kim H, Rho J. Regulation of Osteoclast Differentiation by Cytokine Networks. Immune Netw 2018; 18:e8. [PMID: 29503739 PMCID: PMC5833125 DOI: 10.4110/in.2018.18.e8] [Citation(s) in RCA: 348] [Impact Index Per Article: 49.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/02/2018] [Accepted: 02/03/2018] [Indexed: 12/20/2022] Open
Abstract
Cytokines play a pivotal role in maintaining bone homeostasis. Osteoclasts (OCs), the sole bone resorbing cells, are regulated by numerous cytokines. Macrophage colony-stimulating factor and receptor activator of NF-κB ligand play a central role in OC differentiation, which is also termed osteoclastogenesis. Osteoclastogenic cytokines, including tumor necrosis factor-α, IL-1, IL-6, IL-7, IL-8, IL-11, IL-15, IL-17, IL-23, and IL-34, promote OC differentiation, whereas anti-osteoclastogenic cytokines, including interferon (IFN)-α, IFN-β, IFN-γ, IL-3, IL-4, IL-10, IL-12, IL-27, and IL-33, downregulate OC differentiation. Therefore, dynamic regulation of osteoclastogenic and anti-osteoclastogenic cytokines is important in maintaining the balance between bone-resorbing OCs and bone-forming osteoblasts (OBs), which eventually affects bone integrity. This review outlines the osteoclastogenic and anti-osteoclastogenic properties of cytokines with regard to osteoimmunology, and summarizes our current understanding of the roles these cytokines play in osteoclastogenesis.
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Affiliation(s)
| | - Hyeongseok Yun
- Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 34134, Korea
| | - Sumi Kim
- Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 34134, Korea
| | - Nari Lee
- Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 34134, Korea
| | - Hyunjong Kim
- Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 34134, Korea
| | - Jaerang Rho
- Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 34134, Korea
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17
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Paradowska-Gorycka A, Sowinska A, Stypinska B, Grobelna MK, Walczyk M, Olesinska M, Piotrowski P, Jagodzinski PP. Genetic Variants in IL-12B and IL-27 in the Polish Patients with Systemic Lupus Erythematosus. Scand J Immunol 2017; 84:49-60. [PMID: 27059274 DOI: 10.1111/sji.12439] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 04/04/2016] [Indexed: 01/12/2023]
Abstract
To investigate the potential association between IL-12B and IL-27 gene polymorphisms and systemic lupus erythematosus (SLE), we performed a case-control study based on the Polish population. Patients with SLE and healthy individuals were examined for -6415 CTCTAA/GC (rs17860508) and +1188A/C (rs3212227) in IL-12B and -924A/G (rs153109) and 4730T/C (rs181206) in IL-27 gene polymorphisms using the high-resolution melting method, PCR-RFLP method and TaqMan SNP genotyping assay, respectively. An increased frequency of GC/GC genotype as well as GC allele of the IL-12B rs17860508 was found in patients with SLE, as compared with healthy subjects (P < 0.001). We did not find differences in genotype and allele frequencies of the IL-12B rs3212227 and IL-27 rs153109 and rs181206 variants between patients with SLE and controls. IL-27 haplotype rs181206C/rs153109G indicated higher risk for SLE (P = 0.002), whereas haplotype rs181206T/rs153109G indicated reduced risk for SLE (P = 0.005). The IL-12B rs3212227 A/C polymorphism was associated with the mean value of the platelets (PLT), urea and complement C3 level. Furthermore, IL-12B rs17860508 genetic variant showed correlation with PLT, prothrombin time, international normalized ratio and alkaline phosphatase. Our results revealed that IL-12B rs17860508 and IL-27 haplotype CG are genetic risk factors for SLE and that both IL-12B rs17860508 and rs3212227 predict disease phenotype.
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Affiliation(s)
- A Paradowska-Gorycka
- Department of Biochemistry and Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - A Sowinska
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, Poznan, Poland
| | - B Stypinska
- Department of Biochemistry and Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - M K Grobelna
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland
| | - M Walczyk
- Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - M Olesinska
- Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - P Piotrowski
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland.,Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - P P Jagodzinski
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland
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18
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Sharma J, Bhar S, Devi CS. A review on interleukins: The key manipulators in rheumatoid arthritis. Mod Rheumatol 2017; 27:723-746. [DOI: 10.1080/14397595.2016.1266071] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Jatin Sharma
- School of Biosciences and Technology, VIT University, Vellore, India
| | - Sutonuka Bhar
- School of Biosciences and Technology, VIT University, Vellore, India
| | - C. Subathra Devi
- School of Biosciences and Technology, VIT University, Vellore, India
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19
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Sims NA. Cell-specific paracrine actions of IL-6 family cytokines from bone, marrow and muscle that control bone formation and resorption. Int J Biochem Cell Biol 2016; 79:14-23. [PMID: 27497989 DOI: 10.1016/j.biocel.2016.08.003] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 08/01/2016] [Accepted: 08/03/2016] [Indexed: 12/27/2022]
Abstract
Bone renews itself and changes shape throughout life to account for the changing needs of the body; this requires co-ordinated activities of bone resorbing cells (osteoclasts), bone forming cells (osteoblasts) and bone's internal cellular network (osteocytes). This review focuses on paracrine signaling by the IL-6 family of cytokines between bone cells, bone marrow, and skeletal muscle in normal physiology and in pathological states where their levels may be locally or systemically elevated. These functions include the support of osteoclast formation by osteoblast lineage cells in response to interleukin 6 (IL-6), interleukin 11 (IL-11), oncostatin M (OSM) and cardiotrophin 1 (CT-1). In addition it will discuss how bone-resorbing osteoclasts promote osteoblast activity by secreting CT-1, which acts as a "coupling factor" on osteocytes, osteoblasts, and their precursors to promote bone formation. OSM, produced by osteoblast lineage cells and macrophages, stimulates bone formation via osteocytes. IL-6 family cytokines also mediate actions of other bone formation stimuli like parathyroid hormone (PTH) and mechanical loading. CT-1, OSM and LIF suppress marrow adipogenesis by shifting commitment of pluripotent precursors towards osteoblast differentiation. Ciliary neurotrophic factor (CNTF) is released as a myokine from skeletal muscle and suppresses osteoblast differentiation and bone formation on the periosteum (outer bone surface in apposition to muscle). Finally, IL-6 acts directly on marrow-derived osteoclasts to stimulate release of "osteotransmitters" that act through the cortical osteocyte network to stimulate bone formation on the periosteum. Each will be discussed as illustrations of how the extended family of IL-6 cytokines acts within the skeleton in physiology and may be altered in pathological conditions or by targeted therapies.
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Affiliation(s)
- Natalie A Sims
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Victoria, Australia.
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20
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Alves CH, Farrell E, Vis M, Colin EM, Lubberts E. Animal Models of Bone Loss in Inflammatory Arthritis: from Cytokines in the Bench to Novel Treatments for Bone Loss in the Bedside-a Comprehensive Review. Clin Rev Allergy Immunol 2016; 51:27-47. [PMID: 26634933 PMCID: PMC4961736 DOI: 10.1007/s12016-015-8522-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Throughout life, bone is continuously remodelled. Bone is formed by osteoblasts, from mesenchymal origin, while osteoclasts induce bone resorption. This process is tightly regulated. During inflammation, several growth factors and cytokines are increased inducing osteoclast differentiation and activation, and chronic inflammation is a condition that initiates systemic bone loss. Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that is characterised by active synovitis and is associated with early peri-articular bone loss. Peri-articular bone loss precedes focal bone erosions, which may progress to bone destruction and disability. The incidence of generalised osteoporosis is associated with the severity of arthritis in RA and increased osteoporotic vertebral and hip fracture risk. In this review, we will give an overview of different animal models of inflammatory arthritis related to RA with focus on bone erosion and involvement of pro-inflammatory cytokines. In addition, a humanised endochondral ossification model will be discussed, which can be used in a translational approach to answer osteoimmunological questions.
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Affiliation(s)
- C Henrique Alves
- Department of Rheumatology, Erasmus MC, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Eric Farrell
- Department of Oral and Maxillofacial Surgery, Special Dental Care and Orthodontics, Erasmus MC, University Medical Center, Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Marijn Vis
- Department of Rheumatology, Erasmus MC, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Edgar M Colin
- Department of Rheumatology, Erasmus MC, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
- Department of Rheumatology, ZGT Almelo, Zilvermeeuw 1, 7600 SZ, Almelo, The Netherlands
| | - Erik Lubberts
- Department of Rheumatology, Erasmus MC, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
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21
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Bergamini A, Bolacchi F, Pesce CD, Veneziano G, Uccioli L, Girardi V, De Corato L, Mondillo MT, Squillaci E. Expression of the receptor activator of nuclear factor-kB ligand in peripheral blood mononuclear cells in patients with acute Charcot neuroarthropathy. Int J Med Sci 2016; 13:875-880. [PMID: 28090190 PMCID: PMC5236002 DOI: 10.7150/ijms.14579] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 07/08/2016] [Indexed: 11/06/2022] Open
Abstract
Introduction. The receptor activator of nuclear factor-kB (RANK), ligand (RANK-L) and osteoprotegerin (OPG) are implicated in the pathogenesis of acute Charcot neuroarthropathy (CN). Materials and Methods. This study aimed to investigate the expression of RANK-L and OPG in peripheral blood mononuclear cells (PBMC) from patients with acute CN. Results. We found that the expression of RANK-L was lower in patients with acute CN as compared with diabetic control subjects and healthy control participants; whereas OPG expression was not detected in patients and in both control groups. RANK-L expression at the onset of disease was inversely correlated with the index of polyunsaturation (PUI), a bone marrow MRS-derived measurable index that allows evaluation of disease activity in acute CN, and recovery time. Finally, the expression of RANK-L increased at the time of healing compared with the values found during the acute phase. Conclusions. In conclusion, our preliminary data provide a first step in applying analysis of RANK-L expression in peripheral blood cells to the diagnosis of acute CN. Based on our data we also suggest that analysis of RANK-L expression could be a complementary tool that can be employed to obtain quantitative parameters that may help clinicians to monitor disease activity in patients with acute CN.
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Affiliation(s)
- Alberto Bergamini
- Department of Internal Medicine, Hematology/Oncology Unit, Tor Vergata University, Rome, Italy Department of Public Health and Cellular Biology, University of Rome "Tor Vergata", Rome, Italy
| | - Francesca Bolacchi
- Department of Diagnostic and Molecular Imaging, Radiation Therapy and Interventional Radiology, University Hospital Tor Vergata, Rome, Italy
| | - Caterina Delfina Pesce
- Department of Internal Medicine, Hematology/Oncology Unit, Tor Vergata University, Rome, Italy Department of Public Health and Cellular Biology, University of Rome "Tor Vergata", Rome, Italy
| | - Giada Veneziano
- Department of Internal Medicine, Hematology/Oncology Unit, Tor Vergata University, Rome, Italy Department of Public Health and Cellular Biology, University of Rome "Tor Vergata", Rome, Italy
| | - Luigi Uccioli
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Valentina Girardi
- Department of Diagnostic and Molecular Imaging, Radiation Therapy and Interventional Radiology, University Hospital Tor Vergata, Rome, Italy
| | - Laura De Corato
- Department of Diagnostic and Molecular Imaging, Radiation Therapy and Interventional Radiology, University Hospital Tor Vergata, Rome, Italy
| | - Maria Teresa Mondillo
- Department of Diagnostic and Molecular Imaging, Radiation Therapy and Interventional Radiology, University Hospital Tor Vergata, Rome, Italy
| | - Ettore Squillaci
- Department of Diagnostic and Molecular Imaging, Radiation Therapy and Interventional Radiology, University Hospital Tor Vergata, Rome, Italy
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22
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Meka RR, Venkatesha SH, Dudics S, Acharya B, Moudgil KD. IL-27-induced modulation of autoimmunity and its therapeutic potential. Autoimmun Rev 2015; 14:1131-1141. [PMID: 26253381 PMCID: PMC4628569 DOI: 10.1016/j.autrev.2015.08.001] [Citation(s) in RCA: 149] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 08/01/2015] [Indexed: 11/26/2022]
Abstract
Interleukin-27 (IL-27) is a new member of the IL-12 family. It is produced by activated antigen-presenting cells and plays an important role in the regulation of CD4+ T cell differentiation and immune response. IL-27 activates multiple signaling cascades, including the JAK-STAT and p38 MAPK pathways. Several studies have revealed that IL-27 promotes the differentiation of Th1 and Tr1, but inhibits Th2, Th17, and Treg cells. However, a few studies have shown an opposite effect on certain T cell subsets, such as Treg. IL-27 displays both pro- and anti- inflammatory activities in different autoimmune diseases. Here, we have discussed the role of IL-27 in rheumatoid arthritis, multiple sclerosis, colitis, lupus, psoriasis, type 1 diabetes, and uveitis. Most of this information is derived from experimental models of these autoimmune diseases. The mechanistic basis of the dual role of IL-27 in inflammation and autoimmunity is still not fully defined. In general, the pro-/anti-inflammatory activity of IL-27 is influenced by the underlying immune effector pathways, the phase of the disease, the presence or absence of counter-regulatory cytokines/T cell subsets, and the tissue/cell type under study. Despite a spectrum of outcomes in various autoimmune diseases, mostly anti-inflammatory and immunomodulatory effects of IL-27 have been observed in this category of diseases. Accordingly, IL-27 represents a novel, promising target/agent for the treatment of autoimmune diseases.
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Affiliation(s)
- Rakeshchandra R. Meka
- Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 W. Baltimore Street, HSF-1, Suite 380, Baltimore, MD 21201, USA
| | - Shivaprasad H. Venkatesha
- Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 W. Baltimore Street, HSF-1, Suite 380, Baltimore, MD 21201, USA
| | - Steven Dudics
- Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 W. Baltimore Street, HSF-1, Suite 380, Baltimore, MD 21201, USA
| | - Bodhraj Acharya
- Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 W. Baltimore Street, HSF-1, Suite 380, Baltimore, MD 21201, USA
| | - Kamal D. Moudgil
- Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 W. Baltimore Street, HSF-1, Suite 380, Baltimore, MD 21201, USA
- Division of Rheumatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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23
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Rohmah RN, Hardiyanti F, Fatchiyah F. Inhibition on JAK-STAT3 Signaling Transduction Cascade Is Taken by Bioactive Peptide Alpha-S2 Casein Protein from Goat Ethawah Breed Milk. Acta Inform Med 2015; 23:233-8. [PMID: 26483598 PMCID: PMC4584083 DOI: 10.5455/aim.2015.23.233-238] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 05/15/2015] [Indexed: 01/16/2023] Open
Abstract
Background: RA is a systemic inflammatory disease that causes developing comorbidity conditions. This condition can cause by overproduction of pro-inflammatory cytokine. In a previous study, we have found bioactive peptide CSN1S2 from Ethawah goat milk for anti-inflammatory for repair the ileum destruction. However, the signaling transduction cascade of bioactive peptides inhibits inflammation still not clear yet. Therefore, we analyzed the signaling transduction cascade via JAK-STAT3 pathway by in vivo and in silico. Methods: The ileum was isolated DNA and amplification with specific primer. The sequence was analyzed using the Sanger sequencing method. Modeling 3D-structure was predicted by SWISS-MODEL and virtual interaction was analyzed by docking system using Pymol and Discovery Studio 4.0 software. Results: This study showed that STAT3 has target gene 480bp. The normal group and normal treating- CSN1S2 of goat milk have similarity from gene bank. Whereas, RA group had transversion mutation that the purine change into pyrimidine even cause frameshift mutation. Interestingly, after treating with the CSN1S2 protein of goat milk shows reverse to the normal acid sequence group. Based on in silico study, from eight peptides, only three peptides of CSN1S2 protein, which carried by PePT1 to enter the small intestine. The fragments are PepT1-41-NMAIHPR-47; PepT1-182-KISQYYQK-189 and PepT1-214-TNAIPYVR-221. We have found just one bioactive peptide of f182-KISQYYQK-189 is able bind to STAT3. The energy binding of f182-KISQYYQK-189 and RA-STAT3 amino acid, it was Σ = -402.43 kJ/mol and the energy binding of f182-KISQYYQK-189 and RAS-STAT3 amino acid is decreasing into Σ = -407.09 kJ/mol. Conclusion: This study suggested that the fragment 182-KISQYYQK-189 peptides from Ethawah goat milk may act as an anti-inflammatory agent via JAK-STAT3 signal transduction cascade at the cellular level.
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Affiliation(s)
- Rista Nikmatu Rohmah
- Department of Biology, Faculty of Science, Brawijaya University, Jl. Veteran, Malang 65145, East Java, Indonesia
| | - Ferlany Hardiyanti
- Department of Biology, Faculty of Science, Brawijaya University, Jl. Veteran, Malang 65145, East Java, Indonesia
| | - Fatchiyah Fatchiyah
- Department of Biology, Faculty of Science, Brawijaya University, Jl. Veteran, Malang 65145, East Java, Indonesia
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24
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Aparicio-Siegmund S, Garbers C. The biology of interleukin-27 reveals unique pro- and anti-inflammatory functions in immunity. Cytokine Growth Factor Rev 2015. [PMID: 26195434 DOI: 10.1016/j.cytogfr.2015.07.008] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Interleukin (IL)-27 is a multifaceted heterodimeric cytokine with pronounced pro- and anti-inflammatory as well as immunoregulatory functions. It consists of the two subunits p28/IL-30 and Epstein Bar virus-induced protein 3 (EBI3). EBI3 functions as a soluble α-receptor, and IL-27 can therefore directly activate its target cells through a heterodimer of glycoprotein 130 (gp130) and WSX-1. Being a heterodimeric cytokine that signals through gp130, IL-27 is either grouped into the IL-6 or the IL-12 family of cytokines. Originally identified as an IL-12-like cytokine that induces proliferation of CD4+ T cells and production of IFN-γ more than ten years ago, subsequent research revealed a much broader role of IL-27 in inflammation, cancer development and regulation and differentiation of immune cells. In this review, we summarize the current biochemical and molecular knowledge about the signal transduction of IL-27. Based on this, we highlight functional overlaps and plasticity with other cytokines and cytokine receptors of the IL-6/IL-12 superfamily, and describe the important role of IL-27 with regard to the differentiation of T cells, infections and cancer development. We further discuss IL-27 as a therapeutic target and how specific blockade of this cytokine could be achieved.
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Affiliation(s)
| | - Christoph Garbers
- Institute of Biochemistry, Kiel University, Olshausenstrasse 40, Kiel 24098, Germany.
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25
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Ortiz MA, Diaz-Torné C, Hernández MV, Reina D, de la Fuente D, Castellví I, Moya P, Ruiz JM, Corominas H, Zamora C, Cantó E, Sanmartí R, Juarez C, Vidal S. IL-6 blockade reverses the abnormal STAT activation of peripheral blood leukocytes from rheumatoid arthritis patients. Clin Immunol 2015; 158:174-182. [PMID: 25847223 DOI: 10.1016/j.clim.2015.03.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 03/27/2015] [Accepted: 03/28/2015] [Indexed: 12/22/2022]
Abstract
Considering the interplay of multiple STATs in response to cytokines, we investigated how IL-6 and its blocking affect STAT signaling in rheumatoid arthritis (RA). Leukocytes obtained from RA patients before and after tocilizumab treatment and healthy donors (HDs) were cytokine-stimulated and STAT phosphorylation was analyzed by cytometry. RA patients had significantly fewer pSTAT1+, pSTAT3+, and pSTAT6+ monocytes and pSTAT5+ lymphocytes than HDs. After 24weeks of treatment, percentages of IFNγ-induced pSTAT1+ and IL-10-induced pSTAT3+ monocytes in RA patients increased, reaching levels comparable to HDs. pSTAT1+ and pSTAT3+ cells correlated inversely with RA disease activity index and levels of pSTAT+ cells at baseline were higher in patients with good EULAR response to tocilizumab. IFNγ-induced pSTAT1+ cells correlated inversely with memory T cells and anti-CCP levels. IL-10-induced pSTAT3+ cells correlated with Treg/Teff ratio. Our findings suggest that IL-6 blocking reduces the inflammatory mechanisms through the correction of STAT1 and STAT3 activation status.
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Affiliation(s)
- M A Ortiz
- IIB-Institut Recerca Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
| | - C Diaz-Torné
- Unit of Rheumatology, Department of Internal Medicine, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
| | - M V Hernández
- Arthritis Unit, Rheumatology Department, Hospital Clinic, Barcelona, Spain
| | - D Reina
- Department of Rheumatology, Hospital Moises Broggi, Sant Joan Despí, Spain
| | - D de la Fuente
- Department of Rheumatology, Hospital de Viladecans, Viladecans, Spain
| | - I Castellví
- Department of Rheumatology, Hospital Comarcal de l'Alt Penedes, Vilafranca del Penedes, Spain
| | - P Moya
- Unit of Rheumatology, Department of Internal Medicine, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
| | - J M Ruiz
- Department of Rheumatology, Hospital de Viladecans, Viladecans, Spain
| | - H Corominas
- Department of Rheumatology, Hospital Moises Broggi, Sant Joan Despí, Spain
| | - C Zamora
- IIB-Institut Recerca Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
| | - E Cantó
- IIB-Institut Recerca Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
| | - R Sanmartí
- Arthritis Unit, Rheumatology Department, Hospital Clinic, Barcelona, Spain
| | - C Juarez
- Department of Immunology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - S Vidal
- IIB-Institut Recerca Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
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26
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Targeting JAK kinase in solid tumors: emerging opportunities and challenges. Oncogene 2015; 35:939-51. [DOI: 10.1038/onc.2015.150] [Citation(s) in RCA: 153] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 03/24/2015] [Accepted: 03/24/2015] [Indexed: 02/07/2023]
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Paradowska-Gorycka A, Raszkiewicz B, Jurkowska M, Felis-Giemza A, Romanowska-Prochnicka K, Mańczak M, Olesinska M. Association of single nucleotide polymorphisms in the IL27 gene with rheumatoid arthritis. Scand J Immunol 2014; 80:298-305. [PMID: 25041531 DOI: 10.1111/sji.12209] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Accepted: 06/24/2014] [Indexed: 02/03/2023]
Abstract
Rheumatoid arthritis (RA) is one of the autoimmune diseases, where different polymorphisms in cytokine genes play a pathogenic role. Interleukin 27 (IL-27) is a novel pro-/anti-inflammatory cytokine, an excellent candidate for chronic inflammatory disease studies. The aim of the study was to identify polymorphisms in the IL-27 gene and their possible association with susceptibility to and severity of RA. Two hundred and seventy-four patients with RA and of 295 healthy individuals were examined for -924A/G and 4730T/C IL27 gene polymorphisms using PCR-RFLP method and TaqMan SNP genotyping assay, respectively. Haplotype frequencies of IL-27 polymorphisms were estimated using SHEsis platform. Frequencies of the -924GG genotype and the -924G allele were statistically higher in RA patients comparing with the healthy control group (P = 0.008 and P = 0.004, respectively). Overall, strong LD was observed between the IL27 gene -924A/G and 4730 T/C polymorphisms (D' = 0.613, r2 = 0.199). From four possible haplotypes, frequencies of two (CA and CG) showed significant differences between both examined groups (respectively: P < 0.001 and P = 0.001062). The genotype-phenotype analysis showed significant association between the IL-27 4730 T/C polymorphism and HAQ score and means value of the ESR, additionally they revealed that individuals with the polymorphic allele -924G had more advanced disease than wild-type allele carriers. Present findings indicated that IL27 -924A/G polymorphism may be involved in susceptibility to RA in the Polish population.
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Affiliation(s)
- A Paradowska-Gorycka
- Department of Biochemistry and Molecular Biology, Institute of Rheumatology, Warsaw, Poland
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Magyari L, Varszegi D, Kovesdi E, Sarlos P, Farago B, Javorhazy A, Sumegi K, Banfai Z, Melegh B. Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications. World J Orthop 2014; 5:516-536. [PMID: 25232528 PMCID: PMC4133458 DOI: 10.5312/wjo.v5.i4.516] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 04/05/2014] [Accepted: 05/16/2014] [Indexed: 02/06/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease, resulting in a chronic, systemic inflammatory disorder. It may affect many tissues and organs, but it primarily affects the flexible joints. In clinical practice patient care generates many questions about diagnosis, prognosis, and treatment. It is challenging for health care specialists to keep up to date with the medical literature. This review summarizes the pathogenesis, the polymorphisms of interleukin and interleukin genes and the standard available and possible future immunologic targets for RA treatment. The identification of disease-associated interleukin and interleukin receptor genes can provide precious insight into the genetic variations prior to disease onset in order to identify the pathways important for RA pathogenesis. The knowledge of the complex genetic background may prove useful for developing novel therapies and making personalized medicine based on the individual’s genetics.
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29
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Bournazou E, Bromberg J. Targeting the tumor microenvironment: JAK-STAT3 signaling. JAKSTAT 2014; 2:e23828. [PMID: 24058812 PMCID: PMC3710325 DOI: 10.4161/jkst.23828] [Citation(s) in RCA: 149] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 01/30/2013] [Indexed: 11/19/2022] Open
Abstract
Persistent JAK-STAT3 signaling is implicated in many aspects of tumorigenesis. Apart from its tumor-intrinsic effects, STAT3 also exerts tumor-extrinsic effects, supporting tumor survival and metastasis. These involve the regulation of paracrine cytokine signaling, alterations in metastatic sites rendering these permissive for the growth of cancer cells and subversion of host immune responses to create an immunosuppressive environment. Targeting this signaling pathway is considered a novel promising therapeutic approach, especially in the context of tumor immunity. In this article, we will review to what extent JAK-STAT3-targeted therapies affect the tumor microenvironment and whether the observed effects underlie responsiveness to therapy.
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Affiliation(s)
- Eirini Bournazou
- Department of Medicine; Memorial Sloan-Kettering Cancer Center (MSKCC); New York, NY USA
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RANKL expression in periodontal disease: where does RANKL come from? BIOMED RESEARCH INTERNATIONAL 2014; 2014:731039. [PMID: 24719884 PMCID: PMC3955606 DOI: 10.1155/2014/731039] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 01/22/2014] [Indexed: 11/18/2022]
Abstract
Periodontitis is an inflammatory disease characterized by periodontal pocket formation and alveolar bone resorption. Periodontal bone resorption is induced by osteoclasts and receptor activator of nuclear factor-κB ligand (RANKL) which is an essential and central regulator of osteoclast development and osteoclast function. Therefore, RANKL plays a critical role in periodontal bone resorption. In this review, we have summarized the sources of RANKL in periodontal disease and explored which factors may regulate RANKL expression in this disease.
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31
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Mori G, D'Amelio P, Faccio R, Brunetti G. The Interplay between the bone and the immune system. Clin Dev Immunol 2013; 2013:720504. [PMID: 23935650 PMCID: PMC3725924 DOI: 10.1155/2013/720504] [Citation(s) in RCA: 124] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 06/07/2013] [Indexed: 12/27/2022]
Abstract
In the last two decades, numerous scientists have highlighted the interactions between bone and immune cells as well as their overlapping regulatory mechanisms. For example, osteoclasts, the bone-resorbing cells, are derived from the same myeloid precursor cells that give rise to macrophages and myeloid dendritic cells. On the other hand, osteoblasts, the bone-forming cells, regulate hematopoietic stem cell niches from which all blood and immune cells are derived. Furthermore, many of the soluble mediators of immune cells, including cytokines and growth factors, regulate the activities of osteoblasts and osteoclasts. This increased recognition of the complex interactions between the immune system and bone led to the development of the interdisciplinary osteoimmunology field. Research in this field has great potential to provide a better understanding of the pathogenesis of several diseases affecting both the bone and immune systems, thus providing the molecular basis for novel therapeutic strategies. In these review, we reported the latest findings about the reciprocal regulation of bone and immune cells.
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Affiliation(s)
- Giorgio Mori
- Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy
| | - Patrizia D'Amelio
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Roberta Faccio
- Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Giacomina Brunetti
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Piazza Giulio Cesare, 11, 70124 Bari, Italy
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Spanjol J, Celic T, Markic D, Djordjevic G, Maric I, Fuckar Z, Racki S, Bobinac D. Expression of receptor activator of nuclear factor-kappa B ligand in leukocytes during acute kidney rejection after transplantation in rats. Transplant Proc 2013; 45:1766-1770. [PMID: 23769040 DOI: 10.1016/j.transproceed.2012.10.065] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Revised: 09/11/2012] [Accepted: 10/09/2012] [Indexed: 11/23/2022]
Abstract
BACKGROUND Acute cellular rejection of the transplanted kidney is an important cause of impaired graft function. One of the basic characteristics of acute cellular rejection according to the latest Banff classification of renal allograft pathology is the presence of a large number of T lymphocytes in the allografted tissue. Osteoprotegerin, receptor activator of nuclear factor-kappa B (RANK) and RANK ligand (RANKL), three relatively novel members of the tumor necrosis factor superfamily, have crucial roles not only in physiologic and pathologic bone metabolism but also in immunologic processes. The aim of our study was to determine the expression of RANKL and RANK by T lymphocytes and macrophages in acute cellular kidney allograft rejection in rats. METHODS The study included 15 male Wistar rats of 3 months old and 250-300 g as recipients and 15 male DA rats donors of 3 months old; and weight 250-300 g. When animals were sacrificed at 3 weeks to extract the transplanted kidney for pathohistologic analysis and immunoflorescence. all samples showed acute cellular rejection. Kidney sections were examined by dual-labeled immunofluorescence to detect CD4, CD8, or CD68 (red) and RANK or RANKL (green) with coexpressing cells as orange. RESULTS RANKL-positive expression colocalized with CD4(+) and CD8(+) T lymphocytes in acutely rejected kidney tissue. There was no association between CD4(+) and CD8(+) T cells with RANK expression, which was evident by infiltrating CD68-positive macrophages in the kidney tissue interstitium. CONCLUSION RANK and RANKL were expressed by T lymphocytes and macrophages in acute cellular kidney rejection after transplantation in rats.
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Affiliation(s)
- J Spanjol
- Department of Urology, University Hospital of Rijeka, Rijeka, Croatia.
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The emerging role of Interleukin 27 in inflammatory arthritis and bone destruction. Cytokine Growth Factor Rev 2012; 24:115-21. [PMID: 23165310 DOI: 10.1016/j.cytogfr.2012.10.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Accepted: 10/24/2012] [Indexed: 11/24/2022]
Abstract
Although the causes of inflammatory arthritis elude us, aberrant cytokine expression has been linked to joint pathology. Consequently, several approaches in the clinic and/or in clinical trials are targeting cytokines, e.g. tumor necrosis factor (TNF), Interleukin 23 (IL-23) and Interleukin 17 (IL-17), with the goal of antagonizing their respective biologic activity through therapeutic neutralizing antibodies. Such, cytokine signaling-dependent molecular networks orchestrate synovial inflammation on multiple levels including differentiation of myeloid cells to osteoclasts, the central cellular players in arthritis-associated pathologic bone resorption. Hence, understanding of the cellular and molecular mechanisms elicited by synovial cytokine networks that dictate recruitment, differentiation and activation of osteoclast precursors and osteoclasts, respectively, is central to shaping novel therapeutic options for inflammatory arthritis patients. In this article we are discussing the complex signaling interactions involved in the regulation of inflammatory arthritis and it's associated bone loss with a focus on Interleukin 27 (IL-27). The present review will discuss the primary bone-degrading cell, the osteoclast, and on how IL-27, directly or indirectly, modulates osteoclast activity in autoimmune-driven inflammatory joint diseases.
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35
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Anti-cancer versus cancer-promoting effects of the interleukin-17-producing T helper cells. Immunol Lett 2012; 149:123-33. [PMID: 23159638 DOI: 10.1016/j.imlet.2012.11.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Revised: 10/15/2012] [Accepted: 11/05/2012] [Indexed: 12/18/2022]
Abstract
Research on T helper 17 (Th17) cells with regard to immunoediting has revealed elusive results. Whereas enhanced Th17 response and related molecules such as interleukin (IL)-17, IL-21, IL-22, IL-23 and STAT3 accompanied tumor induction and progression, finding that tumor growth/stage was negatively correlated with increased infiltration of Th17 cells in the tumor mass has prompted elucidation of various antitumor mechanisms elicited by Th17 and their related molecules. The pro-tumor efficacy of Th17 response included promotion of neutrophilia and induction of angiogenic (e.g. VEGF, MMP2 and MMP9) and anti-apoptotic factors (e.g. Bcl-XL), as well as expansion and activation of myeloid-derived suppressor cells, which facilitate generation of tumor-specific regulatory T cells. Other tumor immunogenic settings revealed anti-tumor pathways including induction of cytotoxic activity, expression of MHC antigens, the ability Th17 cells to reside within the tumor, and to convert into IFN-γ producers. Notably, Th17 cell related molecules exert indirect pro- or anti-tumor effects via inducing viral persistence or mediating protective mechanisms against bacterial and viral infection. Herein, the recent literature revealing such immunoediting events mediated by Th17 cells and their associated molecules as delivered by various experimental regimens and observed in cancer patient are revised, with a focus on some proposed anti-cancer therapies.
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36
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Hemdan NYA, Birkenmeier G, Wichmann G. Key molecules in the differentiation and commitment program of T helper 17 (Th17) cells up-to-date. Immunol Lett 2012; 148:97-109. [PMID: 23036716 DOI: 10.1016/j.imlet.2012.09.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2012] [Revised: 09/19/2012] [Accepted: 09/21/2012] [Indexed: 01/02/2023]
Abstract
The mechanisms underlying autoimmunity and cancer remain elusive. However, perpendicular evidence has been evolved in the past decade that T helper (Th)17 cells and their related molecules are implicated in initiation and induction of various disease settings including both diseases. Meanwhile, extensive research on Th17 cells elucidated various molecules including cytokines and transcription factors as well as signaling pathways involved in the differentiation, maturation, survival and ultimate commitment of Th17 cells. In the current review, we revise the mechanistic underpinnings delivered by recent research on these molecules in the Th17 differentiation/commitment concert. We emphasize on those molecules proposed as targets for attaining potential therapies of various autoimmune disorders and cancer, aiming both at dampening the dark-side of Th17 repertoire and simultaneously potentiating its benefits in the roster of the antimicrobial response.
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Affiliation(s)
- Nasr Y A Hemdan
- ENT-Research Lab, Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, University of Leipzig, Liebig Str. 21, 04103 Leipzig, Germany.
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37
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Abstract
Chronic inflammation including autoimmune disease is an important risk factor for the development of osteoporosis. Receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) play a central role in osteoclast differentiation and function, and the molecular pathways by which M-CSF and RANKL induce osteoclast differentiation have been analyzed in detail. Proinflammatory cytokines directly or indirectly regulate osteoclastogenesis and bone resorption providing a link between inflammation and osteoporosis. Tumor necrosis factor-α, interleukin (IL)-1, IL-6, and IL-17 are the most important proinflammatory cytokines triggering inflammatory bone loss. Inhibition of these cytokines has provided potent therapeutic effects in the treatment of diseases such as rheumatoid arthritis. Further investigation is needed to understand the pathophysiology and to develop new strategies to treat inflammatory bone loss. This review summarizes new data on inflammatory bone loss obtained in 2011.
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Affiliation(s)
- Tobias Braun
- Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Krankenhausstrasse 12, 91054, Erlangen, Germany
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Yoshimoto T, Xu M, Mizuguchi I, Chiba Y, Kamiya S, Matsui M, Shahrara S, Mizuguchi J. Regulation of inflammatory immune responses leading to the development of bone destructive autoimmune disease rheumatoid arthritis by IL-27. Arthritis Res Ther 2012. [PMCID: PMC3332455 DOI: 10.1186/ar3576] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Astry B, Harberts E, Moudgil KD. A cytokine-centric view of the pathogenesis and treatment of autoimmune arthritis. J Interferon Cytokine Res 2011; 31:927-40. [PMID: 22149412 PMCID: PMC3234492 DOI: 10.1089/jir.2011.0094] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Accepted: 09/09/2011] [Indexed: 12/14/2022] Open
Abstract
Cytokines are immune mediators that play an important role in the pathogenesis of rheumatoid arthritis (RA), an autoimmune disease that targets the synovial joints. The cytokine environment in the peripheral lymphoid tissues and the target organ (the joint) has a strong influence on the outcome of the initial events that trigger autoimmune inflammation. In susceptible individuals, these events drive inflammation and tissue damage in the joints. However, in resistant individuals, the inflammatory events are controlled effectively with minimal or no overt signs of arthritis. Animal models of human RA have permitted comprehensive investigations into the role of cytokines in the initiation, progression, and recovery phases of autoimmune arthritis. The discovery of interleukin-17 (IL-17) and its association with inflammation and autoimmune pathology has reshaped our viewpoint regarding the pathogenesis of arthritis, which previously was based on a simplistic T helper 1 (Th1)-Th2 paradigm. This review discusses the role of the newer cytokines, particularly those associated with the IL-17/IL-23 axis in arthritis. Also presented herein is the emerging information on IL-32, IL-33, and IL-35. Ongoing studies examining the role of the newer cytokines in the disease process would improve understanding of RA as well as the development of novel cytokine inhibitors that might be more efficacious than the currently available options.
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Affiliation(s)
- Brian Astry
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Erin Harberts
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Kamal D. Moudgil
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland
- Division of Rheumatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
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