The Regulation of Skin Fibrosis in Systemic Sclerosis by Extracellular ATP via P2Y2 Purinergic Receptor
| Autor: | Yoko Yokoyama, Sachiko Ogino, Ryoko Torii, Osamu Ishikawa, Sei-ichiro Motegi, Akihiko Uchiyama, Akiko Sekiguchi, Sahori Yamazaki, Akihito Uehara, Chisako Fujiwara, Liyanage Manosika Buddhini Perera, Mari Hosoi |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
P2Y receptor integumentary system Purinergic receptor Cell Biology Dermatology Pharmacology P2 receptor medicine.disease Biochemistry 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine chemistry Fibrosis 030220 oncology & carcinogenesis Extracellular medicine Phosphorylation Receptor Molecular Biology Adenosine triphosphate |
| Zdroj: | Journal of Investigative Dermatology. 139:890-899 |
| ISSN: | 0022-202X |
| Popis: | Tissue injury/hypoxia and oxidative stress induced-extracellular adenosine triphosphate (ATP) can act as damage-associated molecular pattern molecules, which initiate inflammatory response. Our objective was to elucidate the role of extracellular ATP in skin fibrosis in systemic sclerosis (SSc). We identified that hypoxia enhanced ATP release and that extracellular ATP enhanced IL-6 production more significantly in SSc fibroblasts than in normal fibroblasts. There were no significant differences of P2X and P2Y receptor expression levels between normal and SSc fibroblasts. Nonselective P2 receptor antagonist and selective P2Y2 receptor antagonists, kaempferol and AR-C118925XX, significantly inhibited ATP-induced IL-6 production and phosphorylation of p38 in SSc fibroblasts. ATP-induced IL-6 production was significantly inhibited by p38 inhibitors, SB203580, and doramapimod. Collagen type I production in SSc fibroblasts by ATP-induced IL-6/IL-6 receptor trans-signaling was inhibited by kaempferol and SB203580. The amount of ATP in bleomycin-treated skin was increased, and administration of AR-C118925XX significantly inhibited bleomycin-induced dermal fibrosis in mice. These results suggest that vasculopathy-induced hypoxia and oxidative stress might enhance ATP release in the dermis in SSc and that extracellular ATP-induced phosphorylation of p38 via P2Y2 receptor might enhance IL-6 and collagen type I production in SSc fibroblasts. P2Y2 receptor antagonist therapy could be a treatment for skin sclerosis in patients with SSc. |
| Databáze: | OpenAIRE |
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