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. 2016 Feb 2;13(1):91–99. doi: 10.1007/s13770-016-9086-0

STX0119 ameliorates arthritis in SKG mice via inhibiting T helper 17

Faisal Hayat 1, Seung Hoon Lee 2, Eun-Jung Lee 2, Seok Jung Kim 3, KyungAh Jung 4, Soon Kyu Lee 5, Jeehee Youn 6, Jun-Ki Min 7, Mi-La Cho 2,✉, Dong-Yun Shin 1,✉
PMCID: PMC6170988  PMID: 30603389

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease with chronic and excessive inflammation. Upregulation of interleukin (IL)-17 is involved in the pathogenesis of RA. STX0119 is a specific inhibitor of signal transducer and activator of transcription 3 (STAT3) as a potential target for the treatment of RA. STAT3 is a member of DNA-binding molecules that regulates the expression of proinflammatory cytokines involved in the pathogenesis of RA. The objective of this study was to determine whether STX0119 could inhibit STAT3 and IL-17. We demonstrated that STX0119 decreased T helper (Th) 17 differentiation and IL-17 expression in vitro. STX0119 also improved the severity of zymosan induced arthritis and reduced joint inflammation. STX0119 reduced the proliferation of Th17 and phosphorylated STAT3 expression while increasing Treg differentiation and phosphorylated STAT5 expression. Moreover, STX0119 decreased the expression of IL-6 and -17 but not IL-10. These findings suggest that STX0119 can be used to treat autoimmune RA through inhibiting the activation of STAT3.

Keywords: Rheumatoid arthritis, Signal transducer and activator of transcription 3 inhibitor, T helper 17, Treg, Immune modualtion

Footnotes

Faisal Hayat and Seung Hoon Lee contributed equally to this work.

Contributor Information

Mi-La Cho, Phone: 82-2-2258-7467, FAX: 82-2-599-4287, Email: iammila@catholic.ac.kr.

Dong-Yun Shin, Phone: 82-32-899-6111, FAX: 82-32-820-4829, Email: dyshin@gachon.ac.kr.

References

  • 1.van Hamburg JP, Asmawidjaja PS, Davelaar N, Mus AM, Colin EM, Hazes JM, et al. Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis Rheum. 2011;63:73–83. doi: 10.1002/art.30093. [DOI] [PubMed] [Google Scholar]
  • 2.Ziolkowska M, Koc A, Luszczykiewicz G, Ksiezopolska-Pietrzak K, Klimczak E, Chwalinska-Sadowska H, et al. High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol. 2000;164:2832–2838. doi: 10.4049/jimmunol.164.5.2832. [DOI] [PubMed] [Google Scholar]
  • 3.Niu Q, Cai B, Huang ZC, Shi YY, Wang LL. Disturbed Th17/Treg balance in patients with rheumatoid arthritis. Rheumatol Int. 2012;32:2731–2736. doi: 10.1007/s00296-011-1984-x. [DOI] [PubMed] [Google Scholar]
  • 4.Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S, et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature. 2003;426:454–460. doi: 10.1038/nature02119. [DOI] [PubMed] [Google Scholar]
  • 5.Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, et al. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J Exp Med. 2007;204:41–47. doi: 10.1084/jem.20062259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Yoshitomi H, Sakaguchi N, Kobayashi K, Brown GD, Tagami T, Sakihama T, et al. A role for fungal ta-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J Exp Med. 2005;201:949–960. doi: 10.1084/jem.20041758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Cho ML, Kang JW, Moon YM, Nam HJ, Jhun JY, Heo SB, et al. STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J Immunol. 2006;176:5652–5661. doi: 10.4049/jimmunol.176.9.5652. [DOI] [PubMed] [Google Scholar]
  • 8.Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, O’Malley JT, et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol. 2007;178:4901–4907. doi: 10.4049/jimmunol.178.8.4901. [DOI] [PubMed] [Google Scholar]
  • 9.O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science. 2010;327:1098–1102. doi: 10.1126/science.1178334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 2007;282:9358–9363. doi: 10.1074/jbc.C600321200. [DOI] [PubMed] [Google Scholar]
  • 11.Son HJ, Lee J, Lee SY, Kim EK, Park MJ, Kim KW, et al. Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of Th17/Treg balance and osteoclastogenesis. Mediators Inflamm. 2014;2014:973986. doi: 10.1155/2014/973986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Park JS, Kwok SK, Lim MA, Kim EK, Ryu JG, Kim SM, et al. STA-21, a promising STAT-3 inhibitor that reciprocally regulates Th17 and Treg cells, inhibits osteoclastogenesis in mice and humans and alleviates autoimmune inflammation in an experimental model of rheumatoid arthritis. Arthritis Rheumatol. 2014;66:918–929. doi: 10.1002/art.38305. [DOI] [PubMed] [Google Scholar]
  • 13.Matsuno K, Masuda Y, Uehara Y, Sato H, Muroya A, Takahashi O, et al. Identification of a New Series of STAT3 Inhibitors by Virtual Screening. ACS Med Chem Lett. 2010;1:371–375. doi: 10.1021/ml1000273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Ashizawa T, Miyata H, Ishii H, Oshita C, Matsuno K, Masuda Y, et al. Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation. Int J Oncol. 2011;38:1245–1252. doi: 10.3892/ijo.2011.957. [DOI] [PubMed] [Google Scholar]
  • 15.Ashizawa T, Miyata H, Iizuka A, Komiyama M, Oshita C, Kume A, et al. Effect of the STAT3 inhibitor STX-0119 on the proliferation of cancer stem-like cells derived from recurrent glioblastoma. Int J Oncol. 2013;43:219–227. doi: 10.3892/ijo.2013.1916. [DOI] [PubMed] [Google Scholar]
  • 16.Williams RO, Feldmann M, Maini RN. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. 1992;89:9784–9788. doi: 10.1073/pnas.89.20.9784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Camps M, Rückle T, Ji H, Ardissone V, Rintelen F, Shaw J, et al. Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med. 2005;11:936–943. doi: 10.1038/nm1284. [DOI] [PubMed] [Google Scholar]
  • 18.Hickman-Brecks CL, Racz JL, Meyer DM, LaBranche TP, Allen PM. Th17 cells can provide B cell help in autoantibody induced arthritis. J Autoimmun. 2011;36:65–75. doi: 10.1016/j.jaut.2010.10.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Jhun J, Lee SH, Byun JK, Jeong JH, Kim EK, Lee J, et al. Coenzyme Q10 suppresses Th17 cells and osteoclast differentiation and ameliorates experimental autoimmune arthritis mice. Immunol Lett. 2015;166:92–102. doi: 10.1016/j.imlet.2015.05.012. [DOI] [PubMed] [Google Scholar]
  • 20.Chan AC, Iwashima M, Turck CW, Weiss A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell. 1992;71:649–662. doi: 10.1016/0092-8674(92)90598-7. [DOI] [PubMed] [Google Scholar]
  • 21.Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze-Koops H, et al. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum. 2010;62:2876–2885. doi: 10.1002/art.27622. [DOI] [PubMed] [Google Scholar]
  • 22.Yang EJ, Lee J, Lee SY, Kim EK, Moon YM, Jung YO, et al. EGCG attenuates autoimmune arthritis by inhibition of STAT3 and HIF-1a with Th17/Treg control. PLoS One. 2014;9:e86062. doi: 10.1371/journal.pone.0086062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Jhun J, Lee J, Byun JK, Kim EK, Woo JW, Lee JH, et al. Red ginseng extract ameliorates autoimmune arthritis via regulation of STAT3 pathway, Th17/Treg balance, and osteoclastogenesis in mice and human. Mediators Inflamm. 2014;2014:351856. doi: 10.1155/2014/351856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Camporeale A. Poli V. IL-6, IL-17 and STAT3: a holy trinity in auto-immunity. Front Biosci (Landmark Ed) 2012;17:2306–2326. doi: 10.2741/4054. [DOI] [PubMed] [Google Scholar]
  • 25.Niemand C, Nimmesgern A, Haan S, Fischer P, Schaper F, Rossaint R, et al. Activation of STAT3 by IL-6 and IL-10 in primary human macrophages is differentially modulated by suppressor of cytokine signaling 3. J Immunol. 2003;170:3263–3272. doi: 10.4049/jimmunol.170.6.3263. [DOI] [PubMed] [Google Scholar]
  • 26.Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 2009;206:1457–1464. doi: 10.1084/jem.20090207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Wei L, Laurence A, Elias KMO, Shea JJ. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem. 2007;282:34605–34610. doi: 10.1074/jbc.M705100200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Torre D, Tambini R, Aristodemo S, Gavazzeni G, Goglio A, Cantamessa C, et al. Anti-inflammatory response of IL-4, IL-10 and TGF-beta in patients with systemic inflammatory response syndrome. Mediators Inflamm. 2000;9:193–195. doi: 10.1080/09629350020002912. [DOI] [PMC free article] [PubMed] [Google Scholar]

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