Tofacitinib and Metformin Reduce the Dermal Thickness and Fibrosis in Mouse Model of Systemic Sclerosis

Overview

Journal Sci Rep

Specialty Science

Date 2022 Feb 16

PMID 35169250

Authors

Ahmet Karatas

Burak Oz

Cigdem Celik

Zeynel Abidin Akar

Ramazan Fazil Akkoc

Ebru Onalan Etem

Adile Ferda Dagli

Suleyman Serdar Koca

Affiliations

Soon will be listed here.

Abstract

Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is important in the process of inflammation and fibrosis. The adenosine 5'-monophosphate-activated protein kinase (AMPK) enzyme can affect JAK/STAT pathway. Tofacitinib is a pan-JAK inhibitör. Metformin activates AMPK enzyme. We aimed to investigate the therapeutic efficacy of tofacitinib and metformin on IL-17 and TGF-β cytokines, skin fibrosis and inflammation in mouse model of systemic sclerosis (SSc). 40 Balb/c female mice were divided into 4 groups: (control, sham (BLM), tofacitinib and metformin). The mice in the tofacitinib group received oral tofacitinib (20 mg/kg/daily) and mice in the metformin group received oral metformin (50 mg/kg/day) for 28 days. At the end of 4th week, all groups of mice were decapitated and tissue samples were taken for analysis. Histopathological analysis of skin tissue was performed, and mRNA expressions of collagen 3A, IL-17 and TGF-β were assessed by real-time PCR and ELISA. Repeated BLM injections had induced dermal fibrosis. Moreover, the tissue levels of collagen 3A, IL-17 and TGF-β were elevated in the BLM group. Tofacitinib and metformin mitigated dermal fibrosis. They reduced dermal thickness and tissue collagen 3A, IL-17 and TGF-β levels. Tofacitinib and metformin demonstrated anti-inflammatory and anti-fibrotic effects in the mouse model of SSc.

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References

You H, Xu D, Hou Y, Zhou J, Wang Q, Li M . Tofacitinib as a possible treatment for skin thickening in diffuse cutaneous systemic sclerosis. Rheumatology (Oxford). 2020; 60(5):2472-2477. DOI: 10.1093/rheumatology/keaa613. View

Speirs C, Williams J, Riches K, Salt I, Palmer T . Linking energy sensing to suppression of JAK-STAT signalling: A potential route for repurposing AMPK activators?. Pharmacol Res. 2017; 128:88-100. DOI: 10.1016/j.phrs.2017.10.001. View

Eren M, Kuloglu T, Aydin S, Yilmaz M, Gul E, Kalayci M . Alteration of serum and cardiac tissue adropin, copeptin, irisin and TRPM2 expressions in DOX treated male rats. Biotech Histochem. 2014; 90(3):197-205. DOI: 10.3109/10520295.2014.977949. View

Koca S, Ozgen M, Dagli F, Tuzcu M, Ozercan I, Sahin K . Proteasome inhibition prevents development of experimental dermal fibrosis. Inflammation. 2011; 35(3):810-7. DOI: 10.1007/s10753-011-9380-y. View

Pedroza M, Le T, Lewis K, Karmouty-Quintana H, To S, George A . STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation. FASEB J. 2015; 30(1):129-40. PMC: 4684532. DOI: 10.1096/fj.15-273953. View

Kang K, Kim Y, Yi H, Kim J, Jung H, Kim I . Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis. Int Immunopharmacol. 2013; 16(1):85-92. DOI: 10.1016/j.intimp.2013.03.020. View

Clark J, Flanagan M, Telliez J . Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem. 2014; 57(12):5023-38. DOI: 10.1021/jm401490p. View

Fallet B, Walker U . Current immunosuppressive and antifibrotic therapies of systemic sclerosis and emerging therapeutic strategies. Expert Rev Clin Pharmacol. 2020; 13(11):1203-1218. DOI: 10.1080/17512433.2020.1832466. View

Bao L, Zhang H, Chan L . The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT. 2013; 2(3):e24137. PMC: 3772104. DOI: 10.4161/jkst.24137. View

10.

Buran I, Etem E, Tektemur A, Elyas H . Treatment with TREK1 and TRPC3/6 ion channel inhibitors upregulates microRNA expression in a mouse model of chronic mild stress. Neurosci Lett. 2017; 656:51-57. DOI: 10.1016/j.neulet.2017.07.017. View

11.

Morrisroe K, Sudararajan V, Stevens W, Sahhar J, Zochling J, Roddy J . Work productivity in systemic sclerosis, its economic burden and association with health-related quality of life. Rheumatology (Oxford). 2017; 57(1):73-83. DOI: 10.1093/rheumatology/kex362. View

12.

You H, Xu D, Zhao J, Li J, Wang Q, Tian X . JAK Inhibitors: Prospects in Connective Tissue Diseases. Clin Rev Allergy Immunol. 2020; 59(3):334-351. DOI: 10.1007/s12016-020-08786-6. View

13.

Lu J, Shi J, Li M, Gui B, Fu R, Yao G . Activation of AMPK by metformin inhibits TGF-β-induced collagen production in mouse renal fibroblasts. Life Sci. 2015; 127:59-65. DOI: 10.1016/j.lfs.2015.01.042. View

14.

Asano Y . The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies. J Clin Med. 2020; 9(9). PMC: 7565034. DOI: 10.3390/jcm9092687. View

15.

Wang J, Song Y, Li H, Shen Q, Shen J, An X . Exacerbated cardiac fibrosis induced by β-adrenergic activation in old mice due to decreased AMPK activity. Clin Exp Pharmacol Physiol. 2016; 43(11):1029-1037. DOI: 10.1111/1440-1681.12622. View

16.

Seif F, Khoshmirsafa M, Aazami H, Mohsenzadegan M, Sedighi G, Bahar M . The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal. 2017; 15(1):23. PMC: 5480189. DOI: 10.1186/s12964-017-0177-y. View

17.

Wang Y, Zhang S, Liang Z, Feng M, Zhao X, Qin K . Metformin attenuates bleomycin-induced scleroderma by regulating the balance of Treg/Teff cells and reducing spleen germinal center formation. Mol Immunol. 2019; 114:72-80. DOI: 10.1016/j.molimm.2019.07.002. View

18.

Ursini F, Grembiale R, DAntona L, Gallo E, DAngelo S, Citraro R . Oral Metformin Ameliorates Bleomycin-Induced Skin Fibrosis. J Invest Dermatol. 2016; 136(9):1892-1894. DOI: 10.1016/j.jid.2016.05.097. View

19.

Fang S, Huang Y, Wang S, Zhang Y, Luo X, Liu L . IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO. J Clin Endocrinol Metab. 2016; 101(8):2955-65. DOI: 10.1210/jc.2016-1882. View

20.

Wang W, Bhattacharyya S, Marangoni R, Carns M, Dennis-Aren K, Yeldandi A . The JAK/STAT pathway is activated in systemic sclerosis and is effectively targeted by tofacitinib. J Scleroderma Relat Disord. 2022; 5(1):40-50. PMC: 8922593. DOI: 10.1177/2397198319865367. View