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Published on: September 12, 2019
Tofacitinib and metformin reduce the dermal thickness and fibrosis in mouse model of systemic sclerosis
Ahmet Karatas1, Burak Oz2, Cigdem Celik3
1Department of Rheumatology, Firat University School of Medicine, Elazig, Turkey. drakaratas@yahoo.com.
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.
Insights
Tofacitinib and metformin reduced skin fibrosis and inflammation in a mouse model of systemic sclerosis (SSc). Both drugs mitigated dermal thickness and key fibrotic and inflammatory markers, showing therapeutic potential for SSc treatment.
Area of Science:
- Immunology
- Pharmacology
- Dermatology
Background:
- The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is crucial in inflammation and fibrosis.
- Adenosine 5'-monophosphate-activated protein kinase (AMPK) influences the JAK/STAT pathway.
- Tofacitinib inhibits JAK, while metformin activates AMPK.
Purpose of the Study:
- To evaluate the therapeutic effects of tofacitinib and metformin on inflammation and fibrosis in a mouse model of systemic sclerosis (SSc).
- To assess the impact of these drugs on interleukin-17 (IL-17), transforming growth factor-beta (TGF-β), and collagen 3A levels.
Main Methods:
- Forty Balb/c female mice were divided into control, bleomycin (BLM)-induced SSc, tofacitinib-treated, and metformin-treated groups.
- Mice received daily oral doses of tofacitinib (20 mg/kg) or metformin (50 mg/kg) for 28 days.
- Skin fibrosis, dermal thickness, and mRNA expressions of collagen 3A, IL-17, and TGF-β were analyzed using histopathology, real-time PCR, and ELISA.
Main Results:
- Bleomycin injection induced dermal fibrosis, increasing collagen 3A, IL-17, and TGF-β levels.
- Both tofacitinib and metformin treatments significantly reduced dermal thickness and fibrosis.
- Tofacitinib and metformin effectively lowered tissue levels of collagen 3A, IL-17, and TGF-β.
Conclusions:
- Tofacitinib and metformin exhibit significant anti-inflammatory and anti-fibrotic effects in a mouse model of systemic sclerosis.
- These findings suggest that targeting JAK/STAT and AMPK pathways may be a viable therapeutic strategy for SSc.
