Rapid ATP-induced release of matrix metalloproteinase 9 is mediated by the P2X7 receptor.
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.
Gu
Ben J
BJ
Department of Medicine, University of Sydney, Nepean Hospital, Penrith, NSW 2750, Australia.
Wiley
James S
JS
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D007375:Interleukin-1; C546468:P2RX7 protein, human; D010975:Platelet Aggregation Inhibitors; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D020780:Matrix Metalloproteinase 9