CYT387 restores Th17/Treg cell balance and inhibits mature osteoclast cell formation by regulating SOX-5 signaling in rheumatoid arthritis




T helper 17 (Th17) cell, osteoclastogenesis, CYT387, IL-6 trans-signaling, janus kinases, rheumatoid arthritis


The present study was conducted to investigate the therapeutic efficacy of CYT387 in rheumatoid arthritis pathogenesis concerning T helper 17 cell/regulatory T cell (Th17/Treg) imbalance and osteoclastogenesis. In this study, CYT 387 inhibited the proliferation of Th17 cells and collectively relocated FoxP3 + Treg cell differentiation in vitro. CYT387 mitigated the secretion of pathogenic IL-17 via reduced ROR-γt expression and restored the elevated expression of IL-10 by increasing FOXP3 activity. Alternatively, CYT387 abrogated RANKL expression and significantly increased osteoprotegerin levels by reducing SOX-5 activity. Furthermore, in a co-culture system of IL-6 and sIL-6R stimulated adjuvant-induced arthritic fibroblast-like synoviocytes and monocytes/macrophages collected from rat bone marrow, CYT387 reduced osteoclast formation and bone resorptive activity. In conclusion, CYT387 modulated IL-6/sIL-6R dependent JAK1/STAT3 activation and signaling mechanisms in CD4+T cells under Th17 differentiation conditions and osteoclast cells via dampened activation of SOX-5.


Download data is not yet available.


Avci AB, Feist E, Burmester GR. Targeting IL-6 or IL-6 receptor in rheumatoid arthritis: What's the Difference? BioDrugs. 2018; 32: 531-46

Bin Dhuban K, Bartolucci S, d'Hennezel E, Piccirillo CA. Signaling through gp130 compromises suppressive function in human FOXP3+ regulatory T cells. Front Immunol. 2019; 2019.

Chen HL, Lin SC, Li S, Tang KT, Lin CC. Alantolactone alle-viates collagen-induced arthritis and inhibits Th17 cell differentiation through modulation of STAT3 signalling. Pharm Biol. 2021; 59; 132-43.

Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: The interleukin-6 receptor. Rheumatology (Oxford). 2010; 49: 15-24.

Esensten JH, Wofsy D, Bluestone JA. Regulatory T cells as therapeutic targets in rheumatoid arthritis. Nat Rev Rheumatol. 2019; 5: 560-65.

Feng X, Shi Y, Xu L, Peng Q, Wang F, Wang X, Sun W, Lu Y, Tsao BP, Zhang M, Tan W. Modulation of IL-6 induced RANKL expression in arthritic synovium by a transcription factor SOX5. Sci Rep. 2016; 6: 32001.

Gupta V, Mesa RA, Deininger MW, Rivera CE, Sirhan S, Brachmann CB, Colins H, Kawashima J, Xin Y, Verstovsek S. A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis. Haematologica 2017; 102: 94-102.

Hashizume M, Hayakawa N, Mihara M. IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17. Rheumatology (Oxford). 2008; 47: 1635-40.

Jiang Q, Yang G, Liu Q, Wang S, Cui D. Function and role of regulatory T cells in rheumatoid arthritis. Front Immunol. 2021; 12: 626193.

Jones GW, McLoughlin RM, Hammond VJ, Parker CR, Willi-ams JD, Malhotra R, Scheller J, Williams AS, John SR, Topley N, Jones SA. Loss of CD4+ T cell IL-6R expression during inflammation underlines a role for IL-6 trans signaling in the local maintenance of Th17 cells. J Immunol. 2010; 184: 2130-39.

Kim J, Kang S, Kim J, Kwon G, Koo S. Elevated levels of T helper 17 cells are associated with disease activity in patients with rheumatoid arthritis. Ann Lab Med. 2013; 33: 52-59.

Kimura A, Kishimoto T. IL-6: Regulator of Treg/Th17 balance. Eur J Immunol. 2010; 40: 1830-35.

Kondo N, Kuroda T, Kobayashi D. Cytokine networks in the pathogenesis of rheumatoid arthritis. Int J Mol Sci. 2021; 22: 10922.

Kotake S, Yago T, Kobashigawa T, Nanke Y. The plasticity of Th17 cells in the pathogenesis of rheumatoid arthritis. J Clin Med. 2017; 6: 67.

Le Goff B, Bouvard B, Lequerre T, Lespessailles E, Marotte H, Pers YM, Cortet B. Implication of IL-17 in bone loss and structural damage in inflammatory rheumatic diseases. Mediators Inflamm. 2019; 2019.

McInnes IB, Buckley CD, Isaacs JD. Cytokines in rheumatoid arthritis-shaping the immunological landscape. Nat Rev Rheumatol. 2016; 12: 63-68.

McLoughlin RM, Jenkins BJ, Grail D, Williams AS, Fielding CA, Parker CR, Ernst M, Topley N, Jones SA. IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. Proc Natl Acad Sci USA. 2005; 102: 9589-94.

Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev. 2014; 13: 668-77.

Quartuccio L, Zabotti A, Del Zotto S, Zanier L, De Vita S, Valent F. Risk of serious infection among patients receiving biologics for chronic inflammatory diseases: Usefulness of administrative data. J Adv Res. 2018; 15: 87-93.

Samarpita S, Rasool M. Cyanidin restores Th17/Treg balance and inhibits T follicular helper cell differentiation via modulation of ROCK2 signaling in an experimental model of rheumatoid arthritis. Int Immunopharmacol. 2021; 101: 108359.

Shetty A, Hanson R, Korsten P, Shawagfeh M, Arami S, Volkov S, Vila O, Swedler W, Shunaigat AN, Smadi S, Sawaged R, Perkins D, Shahrara S, Sweiss NJ. Tocilizumab in the treatment of rheumatoid arthritis and beyond. Drug Des Devel Ther. 2014; 8: 349-64.

Singh AK, Haque M, Madarampalli B, Shi Y, Wildman B, Basit A, Khuder SA. Prasad B, Hassan Q, Quseph MM, Ahmed S. Ets-2 Propagates IL-6 trans-signaling mediated osteoclast-like changes in human rheumatoid arthritis synovial fibroblast. Front Immunol. 2021; 12: 746503.

Srivastava S, Samarpita S, Ganesan R, Rasool M. CYT387 inhibits the hyperproliferative potential of fibroblast-like synoviocytes via modulation of IL-6/JAK1/STAT3 signaling in rheumatoid arthritis. Immunol Invest. 2022; 51: 1582-97.

Tanaka S, Suto A, Iwamoto T, Kashiwakuma D, Kagami SI, Suzuki K, Takatori H, Tamcahi T, Hirose K, Onodera A, Suzuki J, Ohara O, Yamashimita M, Nakayama T, Nakajima H. Sox5 and c-Maf cooperatively induce Th17 cell differentiation via RORγt induction as downstream targets of Stat3. J Exp Med. 2014; 211: 1857-74.

Tefferi A, Barraco D, Lasho TL, Shah S, Begna KH, Kali AA, Hogan WJ, Litzow MR, Hanson CA, Ketterling RP, Gangat N, Pardanani A. Momelotinib therapy for myelofibrosis: A 7-year follow-up. Blood Cancer J. 2018; 8: 29.

Toh ML, Miossec P. The role of T cells in rheumatoid arthritis: New subsets and new targets. Curr Opin Rheumatol. 2007; 19: 284-88.

Tymoszuk P, Petzer V, Asshoff M. SAT0020 Momelotinib, a janus kinase ½ and activin receptor 1 inhibitor ameliorates joint inflammation, systemic TH17 differentiation and arthritis-linked anemia in preclinical autoimmune RA. Ann Rheum Dis. 2020; 940.

Van Hamburg JP, Tas SW. Molecular mechanisms underpinning T helper 17 cell heterogeneity and functions in rheumatoid arthritis. J Autoimmun. 2018; 87: 69-81.

Verstovsek S, Chen CC, Egyed M, Ellis M, Goh YT, Gupta V, Harrison C, Kiladjian JJ, Lazariou M, Mead A, Mclornan D, McMullin MF, Oh ST, Perkins A, Platzbecker L, Schied C, Vannuchi A, Yoon SS, Kowalski MM, Mesa R. Momelotinib: Momelotinib vs danazol in patients with myelofibrosis previously treated with JAKi who are symptomatic and anemic. Future Oncol. 2021; 17: 1449-58.

Wu Q, Zhou X, Huang D. IL-6 Enhances osteocyte-mediated osteoclastogenesis by promoting JAK2 and RANKL activity in vitro. Cell Physiol Biochem. 2017; 41: 1360-69.

Yang P, Qian FY, Zhang MF, Xu AL, Wang X, Jiang BP, Zhou LL. Th17 cell pathogenicity and plasticity in rheumatoid arthritis. J Leukoc Biol. 2019; 106: 1233-40.

Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich W, Dong C. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 2007; 282: 9358-63.




How to Cite

Srivastava, S., and M. Rasool. “CYT387 Restores Th17/Treg Cell Balance and Inhibits Mature Osteoclast Cell Formation by Regulating SOX-5 Signaling in Rheumatoid Arthritis”. Bangladesh Journal of Pharmacology, vol. 18, no. 4, Dec. 2023, pp. 138-51, doi:10.3329/bjp.v18i4.68901.



Research Articles