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Oncostatin M Suppresses Activation of IL-17/Th17 Via SOCS3 Regulation in CD4+ T Cells

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Oncostatin M Suppresses Activation of IL-17/Th17 Via SOCS3 Regulation in CD4+ T Cells Oncostatin M Suppresses Activation of IL-17/Th17 via SOCS3 Regulation in CD4 + T Cells This information is current as Hye-Jin Son, Seung Hoon Lee, Seon-Yeong Lee, of September 28, 2021. Eun-Kyung Kim, Eun-Ji Yang, Jae-Kyung Kim, Hyeon-Beom Seo, Sung-Hwan Park and Mi-La Cho J Immunol published online 16 January 2017 http://www.jimmunol.org/content/early/2017/01/15/jimmun ol.1502314 Downloaded from Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Author Choice Freely available online through The Journal of Immunology Author Choice option Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts Errata An erratum has been published regarding this article. Please see next page or: /content/198/12/4879.full.pdf The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published January 16, 2017, doi:10.4049/jimmunol.1502314 The Journal of Immunology Oncostatin M Suppresses Activation of IL-17/Th17 via SOCS3 Regulation in CD4+ T Cells Hye-Jin Son,*,1 Seung Hoon Lee,*,1 Seon-Yeong Lee,*,1 Eun-Kyung Kim,* Eun-Ji Yang,* Jae-Kyung Kim,* Hyeon-Beom Seo,* Sung-Hwan Park,*,2 and Mi-La Cho*,†,2 Oncostatin M (OSM) is a pleiotropic cytokine and a member of the IL-6 family. It has both proinflammatory and anti-inflammatory functions and is involved in the activation of STAT3 and STAT5. Rheumatoid arthritis is an autoimmune disease that causes chronic and excessive inflammation. Rheumatoid arthritis can lead to induction of Th17 cells, which express IL-17. The aim of this study was to measure the effects of OSM on the proliferation of regulatory T cells and Th17 cells from mice. IL-2 immune complex suppressed the development of collagen-induced arthritis in mice and altered the regulatory T/Th17 cell balance by increasing OSM expression. OSM mitigated the proliferation of Th17 cells and decreased the expression of IL-17 and IL-21. It promoted the activation of Downloaded from suppressor of cytokine signaling 3 (SOCS3), STAT3, and STAT5. Inhibition of SOCS3, STAT3, and STAT5 lessened the OSM- induced reduction in proliferation of Th17 cells. These observations suggest that OSM can inhibit Th17 differentiation by recip- rocally controlling SOCS3, STAT3, and STAT5. The Journal of Immunology, 2017, 198: 000–000. he distinct cytokines produced by Th cells play significant in Th17 cell differentiation and that the differentiation of Th17 to roles in the immune response and development of auto- Treg cells is regulated by STAT5 (4). The regulation of STAT3 http://www.jimmunol.org/ T immune diseases. Th17 cells are involved in the patho- activation and Th17 cell differentiation are therapeutic targets for genesis of several autoimmune diseases such as rheumatoid several types of autoimmune diseases, and alterations in STAT3 arthritis (RA) by producing IL-17, which induces chronic in- and STAT5 can alter the reciprocal balance between Th17 and flammation and tissue damage in RA patients (1). Regulatory T Treg cells (5, 6). (Treg) cells have immunosuppressive activity by reducing in- Oncostatin M (OSM) is a member of the IL-6 family. Inter- flammation, and there is evidence that Tregs play a significant role estingly, the IL-6 family includes LIF, a known proinflammatory in the immune system through this immunosuppressive effect (2). cytokine that acts as a pleiotropic cytokine and also plays an An imbalance between Th17 and Treg cells and upregulation of important role in inflammatory response. Although IL-6 is by guest on September 28, 2021 Th17 cells in the peripheral blood of RA patients have been primarily considered a proinflammatory cytokine, some IL-6 reported, and an imbalance between these cells is now a signifi- family members also exhibit anti-inflammatory functions (7). cant target for RA therapy (3). OSM has both proinflammatory and anti-inflammatory activi- The proliferation of Th17 and Treg cells is regulated by specific ties (8), and is associated with the activation of transcription transcription factors. It has been suggested that STAT3 is involved factors, including the activation of STAT3 (9). OSM production is mediated by activation of STAT5: STAT5 activation induces OSM expression and deletion of STAT5 decreases OSM ex- *The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-701, South Korea; and †Laboratory of pression (10). Immune Network, Conversant Research Consortium in Immunologic Disease, Col- In this study, we hypothesized that OSM is associated with the lege of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea regulation of STAT3 and STAT5 activation involved in the 1 H.-J.S., S.H.L., and S.-Y.L. contributed equally to this work. proliferation of Th17 and Treg cells. The present investiga- 2S.-H.P. and M.-L.C. contributed equally to this work. tion was conducted to identify whether OSM can regulate the ORCIDs: 0000-0003-4269-8657 (S.-Y.L.); 0000-0003-1711-2060 (S.-H.P.). balance between Th17 and Treg cells. First, we investigated Received for publication October 30, 2015. Accepted for publication December 13, whether OSM could regulate Th17 cells by measuring the ex- 2016. pression of transcription factors in vitro. Second, we evaluated This work was supported by grants from the Korean Health Technology R&D the role of OSM in suppressing the proliferation of Th17 cells Project, Ministry of Health and Welfare, Republic of Korea (HI13C0016 and HI14C3417), and by the Basic Science Research Program through the National andtheconversionofTregintoTh17cells.Tounderstandhow Research Foundation of Korea funded by the Ministry of Science, ICT and OSM downregulates Th17 differentiation, we analyzed the ef- Future Planning (NRF-2015R1C1A2A01051677). fect of OSM on the Th17/Treg cell balance regulated by the Address correspondence and reprint requests to Prof. Mi-La Cho, Conversant Re- activation of STAT3 and STAT5 during inhibition of these search Consortium in Immunologic Disease, College of Medicine, The Catholic University of Korea, 505 Banpo-Dong, Seocho-Ku 137-040, Seoul, South Korea. transcription factors. E-mail address: [email protected] Abbreviations used in this article: CIA, collagen-induced arthritis; CII, collagen type II; IL-2IC, IL-2 immune complex; OSM, oncostatin M; RA, rheumatoid arthritis; Materials and Methods siRNA, small interfering RNA; SOCS3, suppressor of cytokine signaling 3; Treg, Animals regulatory T cell. This article is distributed under The American Association of Immunologists, Inc., Male DBA1/J mice (SLC, Shizuoka, Japan) at 6–8 wk of age were Reuse Terms and Conditions for Author Choice articles. maintained in groups of five in polycarbonate cages in a specific pathogen- free environment. They were fed standard mouse chow (Ralston Purina, Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 Gray Summit, MO) and water ad libitum. All experimental procedures www.jimmunol.org/cgi/doi/10.4049/jimmunol.1502314 2 OSM REDUCES Th17 ACTIVATION VIA SOCS3 REGULATION IN T CELLS were examined and approved by the Animal Research Ethics Committee at Intracellular staining for flow cytometry the Catholic University of Korea. Before cell staining, differentiated CD4+ T cells were stimulated with PMA at 25 ng/ml and ionomycin at 250 ng/ml (both from Sigma) in the presence Immunization with collagen type II and injection of IL-2 of GolgiStop (BD Pharmingen) for 4 h. To analyze intracellular cytokines, immune complex cells were stained with anti-mouse CD4–PerCP, anti-mouse CD25– allophycocyanin, anti-mouse IL-17–FITC, and anti-mouse Foxp3–PE Collagen-induced arthritis (CIA) was induced in DBA1/J mice (n = 10 per (eBiosciences) followed by fixation and permeabilization with a Foxp3 group). Mice were immunized through the base of the tail with 100 mgof staining buffer kit according to the manufacturer’s instructions. All data bovine collagen type II (CII) (Chondrex, Redmond, WA) in CFA or IFA were analyzed using FlowJo software (Tree Star, Ashland, OR). (Chondrex). To study the effects of the IL-2 immune complex (IL-2IC) (IL-2/JES6-1 complexes) on CIA, IL-2IC (1.5 mg/7.5 mg; eBioscience, San Confocal microscopy Diego, CA) or saline as a control were injected i.p. three times at 2-d intervals before the first immunization. For confocal staining, spleen tissues or CD4 T cells were stained with anti- mouse CD4–PE, anti-mouse Foxp3–FITC, anti-mouse CD25–allophyco- Clinical scoring of arthritis cyanin, anti-mouse IL-17–FITC or –PE, and anti-mouse IL-21–FITC (all from eBiosciences). Stained sections were analyzed using a confocal mi- Mice were examined visually twice a week for the appearance of arthritis in croscopy system (LSM 510 Meta; Carl Zeiss, Thornwood, NY). the peripheral joints. The index of arthritis was graded using the method of Williams et al. (11) with the following five grades: grade 0: no evidence of Real-time quantitative PCR erythema or swelling; grade 1: erythema and mild swelling confined to the midfoot (tarsals) or ankle joint; grade 2: erythema and mild swelling The mRNA expression levels were estimated using a LightCycler 2.0 in- extending from the ankle to the midfoot; grade 3: erythema and moderate strument (Roche Diagnostic, Mannheim, Germany) with version 4.0 swelling extending from the ankle to the metatarsal joints; and grade 4: software.
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