Tofacitinib and metformin reduce the dermal thickness and fibrosis in mouse model of systemic sclerosis

• Published in: Scientific reports Vol. 12; no. 1; pp. 2553 - 9
• Main Authors: Karatas, Ahmet, Oz, Burak, Celik, Cigdem, Akar, Zeynel Abidin, Akkoc, Ramazan Fazil, Etem, Ebru Onalan, Dagli, Adile Ferda, Koca, Suleyman Serdar
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 15.02.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adenosine kinase; AMP; Animals; Antidiabetics; Collagen; Drug Therapy, Combination; Enzyme-linked immunosorbent assay; Enzymes; Female; Fibrosis; Fibrosis - drug therapy; Inflammation; Interleukin 17; Janus kinase; Kinases; Metformin; Metformin - pharmacology; Mice; Mice, Inbred BALB C; Piperidines - pharmacology; Protein kinase; Pyrimidines - pharmacology; Scleroderma; Scleroderma, Systemic - drug therapy; Skin; Skin - drug effects; Skin - pathology; Systemic sclerosis; Transcription; Transforming growth factor-b
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-06581-1

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.