P2Y11 receptor antagonist NF340 ameliorates inflammation in human fibroblast-like synoviocytes: An implication in rheumatoid arthritis

• Published in: IUBMB life Vol. 71; no. 10; p. 1552
• Main Authors: Gao, Feng, Li, Xin
• Format: Journal Article
• Language: English
• Published: England 01.10.2019
• Subjects: Animals; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - pathology; Fibroblasts - drug effects; Gene Expression Regulation - drug effects; Humans; Inflammation - drug therapy; Inflammation - genetics; Inflammation - pathology; Inflammation Mediators - pharmacology; Interleukin-1beta - genetics; Matrix Metalloproteinase 1 - genetics; Matrix Metalloproteinase 13 - genetics; Matrix Metalloproteinase 3 - genetics; NF-kappa B - genetics; NF-KappaB Inhibitor alpha - genetics; Oxidative Stress - drug effects; Phosphorylation - drug effects; Promoter Regions, Genetic - drug effects; Purinergic P2Y Receptor Antagonists - pharmacology; Receptors, Purinergic P2 - drug effects; Receptors, Purinergic P2 - genetics; Synoviocytes - drug effects; fibroblast-like synoviocytes (FLS); P2Y11 receptor (P2Y11R); NFκB; IL-1β; NF340
• ISSN: 1521-6551
• DOI: 10.1002/iub.2077

Rheumatoid arthritis is a common chronic inflammatory joint disease. Fibroblast-like synoviocytes-mediated inflammation is closely associated with the development of rheumatoid arthritis. In this study, we report that P2Y11 receptor activity is required for cytokine-induced inflammation in primary fibroblast-like synoviocytes (FLS). P2Y11R is fairly expressed in primary FLS isolated from healthy subjects and is elevated to around three- to four-fold in rheumatoid arthritis-derived FLS. The expression of P2Y11R is inducible upon IL-1β treatment. Blockage of P2Y11R by its antagonist suppresses IL-1β-induced TNF-α and IL-6 induction and ameliorates oxidative stress as determined by levels of cellular ROS and the oxidative byproduct 4-HNE. Moreover, blockage of P2Y11R by NF340 inhibits IL-1β-induced matrix metalloproteinase protein expression as indicated by the levels of MMP-1, MMP-3, and MMP-13. Mechanistically, blockage of P2Y11R mitigates IL-1β-activated NFκB signaling, which was revealed by reduced IκBα phosphorylation, nuclear p65 accumulation, and NFκB promoter activity. Our study provides evidence of a protective mechanism of P2Y11R antagonist NF340 against cytokine-induced inflammation. Therefore, targeting P2Y11R could have potential therapeutic implication in the treatment of RA.