Skip to main content

Advertisement

SpringerLink
Log in

Tofacitinib enhances IGF1 via inhibiting STAT6 transcriptionally activated-miR-425-5p to ameliorate inflammation in RA-FLS

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease, which has been reported closely associated with the dysfunction of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. This study aims to explore the potential therapeutic effect of Tofacitinib, a putative JAK/STAT inhibitor, in RA. Tofacitinib suppressed proliferation and accelerated apoptosis of rheumatoid arthritis synovial fibroblasts (RA-FLS) as confirmed by CCK-8, EdU and Western blot assays. Tofacitinib significantly inhibited expression of pro-inflammatory factors including tumor necrosis factor-α (TNF-α), vascular endothelial growth factor A, matrix metalloproteinase 1, matrix metalloproteinase 3, interleukin-6 and interferon gamma in RA-FLS cells. mechanistically, tofacitinib decreased signal transducer and activator of transcription 6 (STAT6), which transcriptionally activates miR-425-5p, and thus increased insulin like growth factor 1 (IGF1) expression, a target of miR-425-5p in RA-FLS. Overexpression of STAT6 restored the expression of pro-inflammatory factors and proliferation inhibited by Tofacitinib in RA-FLS. Overall, Tofacitinib exerted inhibitory effect on proliferation and inflammation of RA-FLS through modulating STAT6/miR-425-5p/IGF1 signal axis. These findings shed light on the novel strategies for improving RA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

My manuscript has no associated data.

References

  1. Chen X, Li D, Zhang H, Duan Y, Huang Y (2021) Co-amorphous systems of sinomenine with nonsteroidal anti-inflammatory drugs: a strategy for solubility improvement, sustained release, and drug combination therapy against rheumatoid arthritis. Int J Pharm. https://doi.org/10.1016/j.ijpharm.2021.120894

    Article  PubMed  PubMed Central  Google Scholar 

  2. Magne T, Helal-Neto E, Correa L, Rebelo Alencar L, Gemini Piperni S, Iram S, Bhattarai P, Zhu L, Ricci-Junior E, de Oliveira HM, Rosas E, Santos-Oliveira R (2021) Rheumatoid arthritis treatment using hydroxychloroquine and methotrexate co-loaded nanomicelles: in vivo results. Colloids Surf B 206:111952. https://doi.org/10.1016/j.colsurfb.2021.111952

    Article  CAS  Google Scholar 

  3. Lopez-Olivo M, Siddhanamatha H, Shea B, Tugwell P, Wells G, Suarez-Almazor M (2014) Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD000957.pub2

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kaneko Y, Kuwana M, Kameda H, Takeuchi T (2011) Sensitivity and specificity of 2010 rheumatoid arthritis classification criteria. Rheumatology (Oxford) 50:1268–1274. https://doi.org/10.1093/rheumatology/keq442

    Article  Google Scholar 

  5. Schett G (2017) Autoimmunity as a trigger for structural bone damage in rheumatoid arthritis. Mod Rheumatol 27:193–197

    Article  CAS  Google Scholar 

  6. Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM, Holers VM (2017) Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol 31:3–18

    Article  Google Scholar 

  7. Li S, Yu Y, Yue Y, Zhang Z, Su K (2013) Microbial infection and rheumatoid arthritis. J Clin Cell Immunol 4:174

    PubMed  PubMed Central  Google Scholar 

  8. Bermas BL (2014) Non-steroidal anti inflammatory drugs, glucocorticoids and disease modifying anti-rheumatic drugs for the management of rheumatoid arthritis before and during pregnancy. Curr Opin Rheumatol 26:334–340

    Article  CAS  Google Scholar 

  9. Nell V, Machold K, Eberl G, Stamm T, Uffmann M, Smolen J (2004) Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology 43:906–914

    Article  CAS  Google Scholar 

  10. Malemud C (2018) The role of the JAK/STAT signal pathway in rheumatoid arthritis. Ther Adv Musculoskelet Dis 10:117–127. https://doi.org/10.1177/1759720x18776224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Simon L, Taylor P, Choy E, Sebba A, Quebe A, Knopp K, Porreca F (2021) The Jak/STAT pathway: a focus on pain in rheumatoid arthritis. Semin Arthritis Rheum 51:278–284. https://doi.org/10.1016/j.semarthrit.2020.10.008

    Article  CAS  PubMed  Google Scholar 

  12. Delgado-Ramirez Y, Ocaña-Soriano A, Ledesma-Soto Y, Olguín J, Hernandez-Ruiz J, Terrazas L, Leon-Cabrera S (2021) STAT6 is critical for the induction of regulatory T cells in vivo controlling the initial steps of colitis-associated cancer. Int J Mol Sci. https://doi.org/10.3390/ijms22084049

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lee Y, Kim B, Ahn Y, Choi J, Choi Y, Kang J (2021) STAT6 signaling mediates PPARγ activation and resolution of acute sterile inflammation in mice. Cells. https://doi.org/10.3390/cells10030501

    Article  PubMed  PubMed Central  Google Scholar 

  14. Furue M (2020) Regulation of skin barrier function via competition between AHR Axis VERSUS IL-13/IL-4-JAK-STAT6/STAT3 axis: pathogenic and therapeutic implications in atopic dermatitis. J Clin Med. https://doi.org/10.3390/jcm9113741

    Article  PubMed  PubMed Central  Google Scholar 

  15. Świerkot J, Nowak B, Czarny A, Zaczyńska E, Sokolik R, Madej M, Korman L, Sebastian A, Wojtala P, Lubiński Ł, Wiland P (2016) The activity of JAK/STAT and NF-κB in patients with rheumatoid arthritis. Adv Clin Exp Med 25:709–717. https://doi.org/10.17219/acem/61034

    Article  PubMed  Google Scholar 

  16. Hawerkamp H, Domdey A, Radau L, Sewerin P, Oláh P, Homey B, Meller S (2021) Tofacitinib downregulates antiviral immune defence in keratinocytes and reduces T cell activation. Arthritis Res Ther 23:144. https://doi.org/10.1186/s13075-021-02509-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gilmore R, Hilley P, Srinivasan A, Choy M, De Cruz P (2021) Sequential use of high-dose tofacitinib after infliximab salvage therapy in acute severe ulcerative colitis. J Crohns Colitis. https://doi.org/10.1093/ecco-jcc/jjab109

    Article  Google Scholar 

  18. Coates L, Bushmakin A, FitzGerald O, Gladman D, Fallon L, Cappelleri J, Hsu M, Helliwell P (2021) Relationships between psoriatic arthritis composite measures of disease activity with patient-reported outcomes in phase 3 studies of tofacitinib. Arthritis Res Ther 23:94. https://doi.org/10.1186/s13075-021-02474-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yang X, Zhan N, Jin Y, Ling H, Xiao C, Xie Z, Zhong H, Yu X, Tang R, Ma J, Guan J, Yin G, Wu G, Lu L, Wang J (2021) Tofacitinib restores the balance of γδTreg/γδT17 cells in rheumatoid arthritis by inhibiting the NLRP3 inflammasome. Theranostics 11:1446–1457. https://doi.org/10.7150/thno.47860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang Z, Zhan C, Zeng F, Wu S (2020) viaA biopolymer-based and inflammation-responsive nanodrug for rheumatoid arthritis treatment inhibiting JAK-STAT and JNK signalling pathways. Nanoscale 12:23013–23027. https://doi.org/10.1039/d0nr05551d

    Article  CAS  PubMed  Google Scholar 

  21. McGarry T, Orr C, Wade S, Biniecka M, Wade S, Gallagher L, Low C, Veale D, Fearon U (2018) JAK/STAT blockade alters synovial bioenergetics, mitochondrial function, and proinflammatory mediators in rheumatoid arthritis. Arthritis Rheumatol (Hoboken, NJ) 70:1959–1970. https://doi.org/10.1002/art.40569

    Article  CAS  Google Scholar 

  22. Lu H, Guo R, Zhang Y, Su S, Zhao Q, Yu Y, Shi H, Sun H, Zhang Y, Li S, Shi D, Chu X, Sun C (2021) Inhibition of lncRNA TCONS_00077866 ameliorates the high stearic acid diet-induced mouse pancreatic β-cell inflammatory response by increasing miR-297b-5p to downregulate SAA3 expression. Diabetes. https://doi.org/10.2337/db20-1079

    Article  PubMed  Google Scholar 

  23. Jiao P, Wang X, Luoreng Z, Yang J, Jia L, Ma Y, Wei D (2021) miR-223: an effective regulator of immune cell differentiation and inflammation. Int J Biol Sci 17:2308–2322. https://doi.org/10.7150/ijbs.59876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Park J, Shon S, Yoo H, Suh D, Bae D, Shin J, Jun J, Ha N, Song H, Choi Y, Pap T, Song Y (2021) Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis. Arthritis Res Ther 23:177. https://doi.org/10.1186/s13075-021-02561-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ruiz-Roso M, Gil-Zamorano J, de Las L, Hazas M, Tomé-Carneiro J, Crespo M, Latasa M, Briand O, Sánchez-López D, Ortiz A, Visioli F, Martínez J, Dávalos A (2020) Intestinal lipid metabolism genes regulated by miRNAs. Front Genet 11:707. https://doi.org/10.3389/fgene.2020.00707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Emori T, Kasahara M, Sugahara S, Hashimoto M, Ito H, Narumiya S, Higashi Y, Fujii Y (2020) Role of JAK-STAT signaling in the pathogenic behavior of fibroblast-like synoviocytes in rheumatoid arthritis: effect of the novel JAK inhibitor peficitinib. Eur J Pharmacol 882:173238. https://doi.org/10.1016/j.ejphar.2020.173238

    Article  CAS  PubMed  Google Scholar 

  27. Palasiewicz K, Umar S, Romay B, Zomorrodi R, Shahrara S (2021) Tofacitinib therapy intercepts macrophage metabolic reprogramming instigated by SARS-CoV-2 spike protein. Eur J Immunol. https://doi.org/10.1002/eji.202049159

    Article  PubMed  PubMed Central  Google Scholar 

  28. O’Brien A, Hanlon M, Marzaioli V, Wade S, Flynn K, Fearon U, Veale D (2021) Targeting JAK-STAT signalling alters PsA synovial fibroblast pro-inflammatory and metabolic function. Front Immunol 12:672461. https://doi.org/10.3389/fimmu.2021.672461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang L, Hu Y, Song B, Xiong Y, Wang J, Chen D (2021) Targeting JAK/STAT signaling pathways in treatment of inflammatory bowel disease. Inflamm Res. https://doi.org/10.1007/s00011-021-01482-x

    Article  PubMed  PubMed Central  Google Scholar 

  30. Law Y, Lee W, Hsu C, Lin Y, Tsai C, Huang C, Wu M, Tang C, Liu J (2021) miR-let-7c-5p and miR-149-5p inhibit proinflammatory cytokine production in osteoarthritis and rheumatoid arthritis synovial fibroblasts. Aging. https://doi.org/10.18632/aging.203201

    Article  PubMed  PubMed Central  Google Scholar 

  31. Zhang K, Fu W, Zhao S, Jiao T, Wu D, Wang Y (2021) miR-483-3p promotes IL-33 production from fibroblast-like synoviocytes by regulating ERK signaling in rheumatoid arthritis. Inflammation. https://doi.org/10.1007/s10753-021-01503-1

    Article  PubMed  Google Scholar 

  32. Zhang M, Yang P, Shen M, Wang X, Gao N, Zhou X, Zhou L, Lu Y (2021) MicroRNA-26b-5p alleviates murine collagen-induced arthritis by modulating Th17 cell plasticity. Cell Immunol 365:104382. https://doi.org/10.1016/j.cellimm.2021.104382

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

None.

Funding

This work was supported by the National Natural Science Foundation of China (81801596).

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

    Yingjie Liu, Jun Peng, Xiaochuan Xiong & Liang Cheng

  2. Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No.197 Ruijin 2nd Road, Huangpu District, Shanghai, 200092, China

    Xiaobing Cheng

Authors
  1. Yingjie Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaochuan Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaobing Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YJL and XBC conceived the study and designed the experiments. JP, XCX and LC contributed to the data collection, performed the data analysis and interpreted the results. YJL wrote the manuscript; XBC contributed to the critical revision of article. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xiaobing Cheng.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All experimental plans were achieved based on the guidance of Declaration of Helsinki and the approved by the ethics committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. The research objects and their families were informed and they signed a fully-informed consent form.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOC 15 KB)

Supplementary file2 (DOC 20 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Y., Peng, J., Xiong, X. et al. Tofacitinib enhances IGF1 via inhibiting STAT6 transcriptionally activated-miR-425-5p to ameliorate inflammation in RA-FLS. Mol Cell Biochem 477, 2335–2344 (2022). https://doi.org/10.1007/s11010-022-04444-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-022-04444-x

Keywords

Search

Navigation