Selective modulation of MAPKs contribute to the anti-proliferative and anti-inflammatory activities of 1,7-dihydroxy-3,4-dimethoxyxanthone in rheumatoid arthritis-derived fibroblast-like synoviocyte MH7A cells

Abstract

Ethnopharmacological relevance1,7-Dihydroxy-3,4-dimethoxyxanthone (XAN) is an antirheumatic agent isolated from traditional Chinese medicine Securidaca inappendiculata Hassk. This study was designed to investigate its anti-proliferative and anti-inflammatory activities on rheumatoid arthritis derived fibroblast-like synoviocyte cell line MH7A, and explore the underlying mechanism of action. MethodsThe anti-proliferative activity of XAN on MH7A cells was assessed by an MTT method. Its pro-apoptotic and cell cycle arrest activities were analyzed by flow cytometry. W-B method was employed to investigate hallmark kinases involved in the course. Pro-inflammatory cytokines in culture supernatant of MH7A cells were determined by an ELISA method. ResultsThe results showed XAN efficiently suppressed the proliferation and secretion of IL-1β and IL-6 of MH7A cells in a concentration-dependent manner. Co-treatment with MAPKs inhibitors U0126, SB202190 and SP600125 indicated JNK and p38 pathways were involved in the course. Up-regulation of p-p38, p-ERK, bax and p21, and down-regulation of p-JNK, cyclin D1 and bcl-2 were observed upon the treatment with XAN. SB202190 partly reversed the modulatory effects. The results suggested XAN inhibited the proliferation of MH7A cells mainly via cell cycle arrest at G1/S phase, and the activity was due to the up-regulation of p-p38, which led to the modulation of p21 and cyclin D1. The down-regulation of p-JNK by XAN suppressed the secretion of pro-inflammatory cytokines, which was beneficial to the anti-proliferative activity of MH7A cells. ConclusionXAN selectively modulated MAPKs signaling, and exerted the subsequent anti-proliferative and anti-inflammatory activities on MH7A cells.