Rapid ATP-induced release of matrix metalloproteinase 9 is mediated by the P2X7 receptor

Abstract

Matrix metalloproteinase-9 (MMP-9) activity is required for inflammatory response, leukocyte recruitment, and tumor invasion. There is increasing evidence suggesting that the P2X(7) receptor of mononuclear cells, which is activated by extracellular adenosine triphosphate (ATP), is involved in inflammatory responses. In this study, ATP caused a rapid release of MMP-9 and a moderate decrease in tissue inhibitor of metalloproteinase 1 (TIMP-1) release from human peripheral-blood mononuclear cells (PBMCs) over a 30-minute time course. The release was time- and dose-dependent and dissociated from ATP-induced cell death. BzATP, which is the most potent agonist for the P2X(7) receptor, also caused a similar effect at a lower dosage. ATP-induced MMP-9 release was inhibited by the P2X(7) receptor antagonists periodate oxidized ATP and KN-62, or by calcium chelators, as well as by a loss-of-function polymorphism in the P2X(7) receptor, but not by brefeldin A, monensin, or cycloheximide, or by anti-tumor necrosis factor-alpha (TNF-alpha) or anti-interleukin-1beta (IL-1beta) monoclonal antibodies. Results from purified subsets of PBMCs showed monocytes were the major source for MMP-9 and TIMP-1 release, and ATP remained effective in purified monocyte and T-cell populations. These observations suggest a novel role for P2X(7) as a pro-inflammatory receptor involved in rapid MMP-9 release and leukocyte recruitment.