Adenosine inhibits TNF alpha-induced MMP-3 production in MH7A rheumatoid arthritis synoviocytes via A(2A) receptor signaling

Adenosine causes the anti-inflammatory effect of MTX; however, the contributions of synoviocyte adenosine receptors (AdoRs) are unknown, and matrix metalloproteinase 3 (MMP-3) is released by fibroblast-like synoviocytes in response to inflammatory signaling. To understand the mechanism of the clinical observation that the matrix proteinase-3 concentration of patients with rheumatoid arthritis treated successfully with methotrexate does not usually normalize, we investigated the effects of A(2A) AdoR activation and inhibition on tumor necrosis factor-alpha (TNF alpha)-induced MMP-3 release by MH7A human rheumatoid synovial cells. MH7A cells constitutively expressed membrane-associated A(2A) AdoRs, and HENECA enhanced intracellular cAMP. Stimulation with TNF alpha markedly enhanced release of MMP-3 from MH7A cells, whereas HENECA partially and dose-dependently inhibited TNF alpha-evoked MMP-3 release. Similarly, dbcAMP partially inhibited TNF alpha-induced MMP-3 release. Pretreatment with ZM241385 reversed the inhibitory effects of HENECA. Further, TNF alpha induced p38 MAPK and ATF-2 phosphorylation, whereas HENECA suppressed p38 MAPK and ATF-2 phosphorylation. We concluded that adenosine signaling via A(2A) AdoRs, adenylyl cyclase, and cAMP reduces TNF alpha-induced MMP-3 production by interfering with p38 MAPK/ATF-2 activity. Activation of A(2A) AdoR signaling alone using HENECA did not reduce TNF alpha-induced MMP-3 production to the basal levels, which may explain why MTX usually decreases but does not eliminate serum MMP-3.