Abstract
Scleroderma is a chronic fibrotic disease, where proinflammatory and profibrotic events precede collagen accumulation. MKP-1 [mitogen-activated protein kinase (MAPK) phosphatase-1] downregulates inflammatory MAPK pathways suppressing inflammation. MKP-1 also supports Th1 polarization, which could shift Th1/Th2 balance away from profibrotic Th2 profile prevalent in scleroderma. In the present study, we investigated the potential protective role of MKP-1 in scleroderma. We utilized bleomycin-induced dermal fibrosis model as a well-characterized experimental model of scleroderma. Dermal fibrosis and collagen deposition as well as the expression of inflammatory and profibrotic mediators were analyzed in the skin samples. Bleomycin-induced dermal thickness and lipodystrophy were increased in MKP-1-deficient mice. MKP-1 deficiency enhanced collagen accumulation and increased expression of collagens, 1A1 and 3A1, in the dermis. Bleomycin-treated skin from MKP-1-deficient mice also showed enhanced expression of inflammatory and profibrotic factors IL-6, TGF-β1, fibronectin-1 and YKL-40, and chemokines MCP-1, MIP-1α and MIP-2, as compared to wild-type mice. The results show, for the first time, that MKP-1 protects from bleomycin-induced dermal fibrosis, suggesting that MKP-1 favorably modifies inflammation and fibrotic processes that drive the pathogenesis of scleroderma. Compounds enhancing the expression or activity of MKP-1 could thus prevent fibrotic processes in scleroderma and possess potential as a novel immunomodulative drug.
Original language | English |
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Article number | 4668 |
Journal | International Journal of Molecular Sciences |
Volume | 24 |
Issue number | 5 |
DOIs | |
Publication status | Published - 2023 |
Publication type | A1 Journal article-refereed |
Keywords
- cell signaling
- cytokines
- DUSP1
- fibrosis
- inflammation
- MKP-1
- scleroderma
Publication forum classification
- Publication forum level 1
ASJC Scopus subject areas
- Catalysis
- Molecular Biology
- Spectroscopy
- Computer Science Applications
- Physical and Theoretical Chemistry
- Organic Chemistry
- Inorganic Chemistry