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Chatterjee A, Azevedo-Martins JM, Stachler MD. Interleukin-33 as a Potential Therapeutic Target in Gastric Cancer Patients: Current Insights. Onco Targets Ther 2023; 16:675-687. [PMID: 37583706 PMCID: PMC10424681 DOI: 10.2147/ott.s389120] [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: 04/01/2023] [Accepted: 08/06/2023] [Indexed: 08/17/2023] Open
Abstract
Gastric cancer is a significant global health problem as it is the fifth most prevalent cancer worldwide and the fourth leading cause of cancer-related mortality. While cytotoxic chemotherapy remains the primary treatment for advanced GC, response rates are limited. Recent progresses, focused on molecular signalling within gastric cancer, have ignited new hope for potential therapeutic targets that may improve survival and/or reduce the toxic effects of traditional therapies. Carcinomas are generally initiated when critical regulatory genes get mutated, but the progression to malignancy is usually supported by the non-neoplastic cells that create a conducive environment for transformation and progression to occur. Interleukin 33 (IL-33) functions as a dual activity cytokine as it is also a nuclear factor. IL-33 is usually present in the nuclei of the cells. Upon tissue damage, it is released into the extracellular space and binds to its receptor, suppression of tumorigenicity 2 (ST2) L, which is expressed on the membranes of the target cells. IL-33 signalling activates the T Helper 2 (Th2) immune response among other responses. Although the studies on the role of IL-33 in gastric cancer are still in the early stages, they have revealed potentially important (though sometimes conflicting) functions or roles in cancer development and progression. The pro-tumorigenic roles include induction and the recruitment of tumor-associated immune cells, promoting metaplasia progression, and inducing stem cell like and EMT properties in gastric cancer cells. Therapeutic interventions to disrupt these functions may provide a unique strategy for gastric cancer prevention and treatment. This review aims to provide a summary of the role of IL-33 in GC, state its multiple functions in relation to GC, and show potential avenues for promising therapeutic investigation.
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Affiliation(s)
- Annesha Chatterjee
- University of California San Francisco, Department of Pathology, San Francisco, CA, USA
| | | | - Matthew D Stachler
- University of California San Francisco, Department of Pathology, San Francisco, CA, USA
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Pan X, Liu J, Li M, Liang Y, Liu Z, Lao M, Fang M. The association of serum IL-33/ST2 expression with hepatocellular carcinoma. BMC Cancer 2023; 23:704. [PMID: 37507682 PMCID: PMC10375617 DOI: 10.1186/s12885-023-11179-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND IL-33 is a multifunctional cytokine with dual functions. However, the clinicopathological and prognostic significance of IL-33 in cancer patients, especially in patients with hepatocellular carcinoma (HCC), remains controversial. Therefore, we conducted a study of 565 patients with HCC and 561 healthy controls and performed a meta-analysis to quantitatively evaluate the above problems. METHODS We collected blood from 565 patients with HCC and 561 healthy controls. ELISA was used to detect the concentrations of IL-33 and ST2 in the serum, and RT‒PCR was used to detect the levels of IL-33 and ST2 mRNA. Meanwhile, we collected comprehensive literature on IL-33 and the clinical characteristics of cancer patients retrieved from the PubMed, Web of Science and CNKI databases as of December 2022. An odds ratio (OR) with a 95% confidence interval (CI) was used to estimate the impact through overall and stratified analyses. RESULTS Compared with the healthy control group, the levels of ST2 mRNA and serum in the peripheral blood of HCC patients increased (p < 0.05), while the levels of IL-33 mRNA and serum showed no significant difference between the two groups (p > 0.05). In the meta-analysis section, at the tissue level, the overall analysis showed that the expression of IL-33 was positively correlated with tumor stage, histological grade, distant metastasis, and tumor size. Compared with patients with low IL-33 expression, the 3-year overall survival (OS) rate (OR = 3.467, p < 0.001) and 5-year OS rate (OR = 2.784, p < 0.001) of patients with high IL-33 expression were lower. At the serum expression level, the overall analysis showed that the expression of IL-33 increased the risk of cancer, and the serum level of IL-33 was positively correlated with tumor stage and vascular invasion. CONCLUSION IL-33/ST2 is a useful predictive or prognostic biomarker in clinical evaluation and may be used as a potential therapeutic target, but much research is needed to verify this hypothesis.
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Affiliation(s)
- Xiaolan Pan
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi, China
| | - Jinfeng Liu
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi, China
| | - Meiqin Li
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi, China
| | - Yihua Liang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi, China
| | - Zhimin Liu
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi, China
| | - Ming Lao
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi, China.
| | - Min Fang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi, China.
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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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IL-33 promotes gastric tumour growth in concert with activation and recruitment of inflammatory myeloid cells. Oncotarget 2022; 13:785-799. [PMID: 35677533 PMCID: PMC9159270 DOI: 10.18632/oncotarget.28238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 05/07/2022] [Indexed: 01/01/2023] Open
Abstract
Interleukin-33 (IL-33) is an IL-1 family cytokine known to promote T-helper (Th) type 2 immune responses that are often deregulated in gastric cancer (GC). IL-33 is overexpressed in human gastric tumours suggesting a role in driving GC progression although a causal link has not been proven. Here, we investigated the impact of IL-33 genetic deficiency in the well-characterized gp130F/F mouse model of GC. Expression of IL-33 (and it’s cognate receptor, ST2) was increased in human and mouse GC progression. IL-33 deficient gp130F/F/Il33−/− mice had reduced gastric tumour growth and reduced recruitment of pro-tumorigenic myeloid cells including key mast cell subsets and type-2 (M2) macrophages. Cell sorting of gastric tumours revealed that IL-33 chiefly localized to gastric (tumour) epithelial cells and was absent from tumour-infiltrating immune cells (except modest IL-33 enrichment within CD11b+ CX3CR1+CD64+MHCII+ macrophages). By contrast, ST2 was absent from gastric epithelial cells and localized exclusively within the (non-macrophage) immune cell fraction together with mast cell markers, Mcpt1 and Mcpt2. Collectively, we show that IL-33 is required for gastric tumour growth and provide evidence of a likely mechanism by which gastric epithelial-derived IL-33 drives mobilization of tumour-promoting inflammatory myeloid cells.
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Pisani LF, Tontini GE, Gentile C, Marinoni B, Teani I, Nandi N, Creo P, Asti E, Bonavina L, Vecchi M, Pastorelli L. Proinflammatory Interleukin-33 Induces Dichotomic Effects on Cell Proliferation in Normal Gastric Epithelium and Gastric Cancer. Int J Mol Sci 2021; 22:ijms22115792. [PMID: 34071419 PMCID: PMC8197967 DOI: 10.3390/ijms22115792] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 05/08/2021] [Accepted: 05/25/2021] [Indexed: 01/02/2023] Open
Abstract
Interleukin (IL)-33 is a member of the interleukin (IL)-1 family of cytokines linked to the development of inflammatory conditions and cancer in the gastrointestinal tract. This study is designed to investigate whether IL-33 has a direct effect on human gastric epithelial cells (GES-1), the human gastric adenocarcinoma cell line (AGS), and the gastric carcinoma cell line (NCI-N87) by assessing its role in the regulation of cell proliferation, migration, cell cycle, and apoptosis. Cell cycle regulation was also determined in ex vivo gastric cancer samples obtained during endoscopy and surgical procedures. Cell lines and tissue samples underwent stimulation with rhIL-33. Proliferation was assessed by XTT and CFSE assays, migration by wound healing assay, and apoptosis by caspase 3/7 activity assay and annexin V assay. Cell cycle was analyzed by means of propidium iodine assay, and gene expression regulation was assessed by RT-PCR profiling. We found that IL-33 has an antiproliferative and proapoptotic effect on cancer cell lines, and it can stimulate proliferation and reduce apoptosis in normal epithelial cell lines. These effects were also confirmed by the analysis of cell cycle gene expression, which showed a reduced expression of pro-proliferative genes in cancer cells, particularly in genes involved in G0/G1 and G2/M checkpoints. These results were confirmed by gene expression analysis on bioptic and surgical specimens. The aforementioned results indicate that IL-33 may be involved in cell proliferation in an environment- and cell-type-dependent manner.
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Affiliation(s)
- Laura Francesca Pisani
- Gastroenterology ans Endoscopy Unit, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Italy; (L.F.P.); (P.C.)
| | - Gian Eugenio Tontini
- Department of Biomedical Science for Health, Università degli Studi di Milano, 20133 Milano, Italy; (G.E.T.); (C.G.); (B.M.); (I.T.); (N.N.); (E.A.); (L.B.)
- Gastroenterology and Endoscopy Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy;
| | - Carmine Gentile
- Department of Biomedical Science for Health, Università degli Studi di Milano, 20133 Milano, Italy; (G.E.T.); (C.G.); (B.M.); (I.T.); (N.N.); (E.A.); (L.B.)
| | - Beatrice Marinoni
- Department of Biomedical Science for Health, Università degli Studi di Milano, 20133 Milano, Italy; (G.E.T.); (C.G.); (B.M.); (I.T.); (N.N.); (E.A.); (L.B.)
| | - Isabella Teani
- Department of Biomedical Science for Health, Università degli Studi di Milano, 20133 Milano, Italy; (G.E.T.); (C.G.); (B.M.); (I.T.); (N.N.); (E.A.); (L.B.)
| | - Nicoletta Nandi
- Department of Biomedical Science for Health, Università degli Studi di Milano, 20133 Milano, Italy; (G.E.T.); (C.G.); (B.M.); (I.T.); (N.N.); (E.A.); (L.B.)
| | - Pasquale Creo
- Gastroenterology ans Endoscopy Unit, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Italy; (L.F.P.); (P.C.)
| | - Emanuele Asti
- Department of Biomedical Science for Health, Università degli Studi di Milano, 20133 Milano, Italy; (G.E.T.); (C.G.); (B.M.); (I.T.); (N.N.); (E.A.); (L.B.)
- Division of General Surgery, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Italy
| | - Luigi Bonavina
- Department of Biomedical Science for Health, Università degli Studi di Milano, 20133 Milano, Italy; (G.E.T.); (C.G.); (B.M.); (I.T.); (N.N.); (E.A.); (L.B.)
- Division of General Surgery, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Italy
| | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy;
- Gastroenterology and Liver Unit, ASST Santi Paolo e Carlo, Ospedale San Paolo, 20100 Milano, Italy
| | - Luca Pastorelli
- Department of Health Sciences, Università degli Studi di Milano, 20133 Milano, Italy
- Department of Pathophysiology and Trasplantation, Università degli Studi di Milano, 20133 Milano, Italy
- Correspondence: ; Tel.: +39-0252774683
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Huang N, Cui X, Li W, Zhang C, Liu L, Li J. IL‑33/ST2 promotes the malignant progression of gastric cancer via the MAPK pathway. Mol Med Rep 2021; 23:361. [PMID: 33760194 PMCID: PMC7985998 DOI: 10.3892/mmr.2021.12000] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 12/02/2020] [Indexed: 01/18/2023] Open
Abstract
Gastric cancer (GC) remains one of the commonest malignant tumors and the second leading cause of cancer-related deaths worldwide. IL-33 is highly expressed in tumor tissues and serum of patients with GC. However, the function of the IL-33 and IL-33 receptor ST2 in the malignant progression of GC is yet to be elucidated. The present study aimed to explore the effect of the IL-33/ST2 axis on the biological functions of GC cells. The expression of ST2 in GC tissues was measured by immunohistochemistry. GC cell lines (AGS and MKN45) were treated with IL-33, and the expression of ST2 was downregulated by using specific siRNA. The effects of the IL-33/ST2 axis on cell proliferation, migration, invasion, cell cycle and apoptosis was detected by CCK8, Transwell, wound healing, flow cytometry and western blotting assays. The present study found that ST2 was highly expressed in GC tissues compared with normal tissues. IL-33 promoted the proliferation and cell cycle progression of GC cells, and upregulated the expression levels of CDK4, CDK6 and cyclin D1. Furthermore, IL-33 inhibited the apoptosis of GC cells and regulated the expression of apoptosis-associated proteins. In addition, IL-33 stimulated the invasion and migration of GC cells. However, the transfection of ST2 small interfering (si)RNA attenuated the effects of IL-33. Finally, IL-33 stimulation increased the phosphorylation levels of ERK1/2, JNK and p38. The transfection of ST2 siRNA could significantly inhibit the IL-33-induced ERK1/2, JNK and p38 activation. In conclusion, it was found that ST2 was highly expressed in GC tissues. IL-33/ST2 promoted the malignant progression of GC cells by inducing the activation of ERK1/2, JNK and p38.
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Affiliation(s)
- Ning Huang
- Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, P.R. China
| | - Xing Cui
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, P.R. China
| | - Wen Li
- Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, P.R. China
| | - Chunlai Zhang
- Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, P.R. China
| | - Liqing Liu
- Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, P.R. China
| | - Jinxing Li
- Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, P.R. China
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De Salvo C, Pastorelli L, Petersen CP, Buttò LF, Buela KA, Omenetti S, Locovei SA, Ray S, Friedman HR, Duijser J, Xin W, Osme A, Cominelli F, Mahabeleshwar GH, Mills JC, Goldenring JR, Pizarro TT. Interleukin 33 Triggers Early Eosinophil-Dependent Events Leading to Metaplasia in a Chronic Model of Gastritis-Prone Mice. Gastroenterology 2021; 160:302-316.e7. [PMID: 33010253 PMCID: PMC7755675 DOI: 10.1053/j.gastro.2020.09.040] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Interleukin (IL)33/IL1F11 is an important mediator for the development of type 2 T-helper cell (Th2)-driven inflammatory disorders and has also been implicated in the pathogenesis of gastrointestinal (GI)-related cancers, including gastric carcinoma. We therefore sought to mechanistically determine IL33's potential role as a critical factor linking chronic inflammation and gastric carcinogenesis using gastritis-prone SAMP1/YitFc (SAMP) mice. METHODS SAMP and (parental control) AKR mice were assessed for baseline gastritis and progression to metaplasia. Expression/localization of IL33 and its receptor, ST2/IL1R4, were characterized in corpus tissues, and activation and neutralization studies were both performed targeting the IL33/ST2 axis. Dissection of immune pathways leading to metaplasia was evaluated, including eosinophil depletion studies using anti-IL5/anti-CCR3 treatment. RESULTS Progressive gastritis and, ultimately, intestinalized spasmolytic polypeptide-expressing metaplasia (SPEM) was detected in SAMP stomachs, which was absent in AKR but could be moderately induced with exogenous, recombinant IL33. Robust peripheral (bone marrow) expansion of eosinophils and local recruitment of both eosinophils and IL33-expressing M2 macrophages into corpus tissues were evident in SAMP. Interestingly, IL33 blockade did not affect bone marrow-derived expansion and local infiltration of eosinophils, but markedly decreased M2 macrophages and SPEM features, while eosinophil depletion caused a significant reduction in both local IL33-producing M2 macrophages and SPEM in SAMP. CONCLUSIONS IL33 promotes metaplasia and the sequelae of eosinophil-dependent downstream infiltration of IL33-producing M2 macrophages leading to intestinalized SPEM in SAMP, suggesting that IL33 represents a critical link between chronic gastritis and intestinalizing metaplasia that may serve as a potential therapeutic target for preneoplastic conditions of the GI tract.
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Affiliation(s)
| | - Luca Pastorelli
- Department of Pathology; Department of IRCCS Policlinico San Donato, Gastroenterology & Gastrointestinal Endoscopy Unit, San Donato Milanese, 20097 and Department of Biomedical Sciences, University of Milan, Milan, 20122, Italy
| | - Christine P. Petersen
- Department of Department of Surgery and the Epithelial Biology Center, Vanderbilt University, Nashville, TN, 37235, USA
| | - Ludovica F. Buttò
- Department of Medicine/Division of Gastroenterology & Liver Disease, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | | | | | - Silviu A. Locovei
- Department of Pathology; Department of Medicine/Division of Gastroenterology & Liver Disease, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | | | | | | | | | | | - Fabio Cominelli
- Department of Medicine/Division of Gastroenterology & Liver Disease, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | | | - Jason C. Mills
- Department of Medicine, Gastroenterology Division, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - James R. Goldenring
- Department of Department of Surgery and the Epithelial Biology Center, Vanderbilt University, Nashville, TN, 37235, USA
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Afferni C, Buccione C, Andreone S, Galdiero MR, Varricchi G, Marone G, Mattei F, Schiavoni G. The Pleiotropic Immunomodulatory Functions of IL-33 and Its Implications in Tumor Immunity. Front Immunol 2018; 9:2601. [PMID: 30483263 PMCID: PMC6242976 DOI: 10.3389/fimmu.2018.02601] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 10/22/2018] [Indexed: 12/14/2022] Open
Abstract
Interleukin-33 (IL-33) is a IL-1 family member of cytokines exerting pleiotropic activities. In the steady-state, IL-33 is expressed in the nucleus of epithelial, endothelial, and fibroblast-like cells acting as a nuclear protein. In response to tissue damage, infections or necrosis IL-33 is released in the extracellular space, where it functions as an alarmin for the immune system. Its specific receptor ST2 is expressed by a variety of immune cell types, resulting in the stimulation of a wide range of immune reactions. Recent evidences suggest that different IL-33 isoforms exist, in virtue of proteolytic cleavage or alternative mRNA splicing, with potentially different biological activity and functions. Although initially studied in the context of allergy, infection, and inflammation, over the past decade IL-33 has gained much attention in cancer immunology. Increasing evidences indicate that IL-33 may have opposing functions, promoting, or dampening tumor immunity, depending on the tumor type, site of expression, and local concentration. In this review we will cover the biological functions of IL-33 on various immune cell subsets (e.g., T cells, NK, Treg cells, ILC2, eosinophils, neutrophils, basophils, mast cells, DCs, and macrophages) that affect anti-tumor immune responses in experimental and clinical cancers. We will also discuss the possible implications of diverse IL-33 mutations and isoforms in the anti-tumor activity of the cytokine and as possible clinical biomarkers.
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Affiliation(s)
- Claudia Afferni
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy
| | - Carla Buccione
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Sara Andreone
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Maria Rosaria Galdiero
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,WAO Center of Excellence, Naples, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,WAO Center of Excellence, Naples, Italy
| | - Gianni Marone
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,WAO Center of Excellence, Naples, Italy.,Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore", National Research Council, Naples, Italy
| | - Fabrizio Mattei
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Giovanna Schiavoni
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
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