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-offunction polymorphism in the P2X 7 receptor, but not by brefeldin A, monensin, or cycloheximide, or by anti-tumor necrosis factor-␣ (TNF-␣) or anti-interleukin-1␤ (IL-1␤) 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. IntroductionSynthesis and secretion of matrix metalloproteinases (MMPs) have been demonstrated for all cells of the immune and hemopoietic lineages as well as fibroblasts and endothelial cells. A wide variety of neoplastic cells also have been shown to secrete MMPs, and these MMPs are considered to participate in the metastatic dissemination of tumors 1 and cyclic changes in the endometrium. 2 Other studies have shown that MMPs are involved in physiologic processes such as angiogenesis wound repair 3 and the inflammatory response. 4 Among the members of the MMP family, the gelatinases A and B (MMP-2 and 9) are important, since both can produce proteolytic degradation of type 4 collagen, which is the principal component of basement membrane. Many studies have shown that MMP-2 is secreted constitutively, while secretion of MMP-9 is regulated by inflammatory stimuli that differ according to cell type. 5 Like the other MMPs, gelatinases are produced in a latent form containing a prodomain, which requires activation by a cysteine-switch mechanism. 6 Both gelatinases form tight noncovalent and stable complexes with tissue inhibitor of metalloproteinases (TIMPs). Thus, pro-MMP-2 (72 kDa) specifically binds TIMP-2, 7 whereas pro-MMP-9 (92 kDa) specifically binds TIMP-1, which plays a major role in regulating MMP-9 activity. 8 Besides the inhibitory effect of TIMP-1, MMP-9 activity also is regulated at various levels from production to secretion, including transcription of the gene by cytokines such as tumor necrosis factor-␣ (TNF-␣) and interleukin 1␤ (IL-1␤) or by cellular interactions such as cell-cell contact between monocytes and activate...

P2 receptor-mediated signaling in mast cell biology

“…The role of other mast cell-derived cytokines (TNFα, IL-1β, IL-18, IL-25, and IL-33) in asthma pathogenesis was recently reviewed in detail [88,89]. It was also reported that ATP induces the release of matrix metalloproteinase-9 via a P2X 7 -dependent mechanism [95]. Mast cells are a rich source of this enzyme that participates in extracellular matrix remodeling by catalyzing the degradation of type IV collagen, the main component of the basement membrane [96].…”

Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses

“…Besides the caspase-1 dependent processes described above, P2X7 receptor activation has also been shown to signal caspase-1 and IL-1β/IL-18 independent release of cathepsins [111,112], prostaglandin (PG)E 2 [8], phosphatidylserine [113], and matrix metalloproteinase 9 [114], all of which are implicated in cellular processes that play a defined role in inflammation.…”

“…Prolonged stimulation with ATP also leads to caspase-1 dependent, but IL-1β and IL-18 cytokine processing independent cell death in macrophages [87,98,99]. b P2X7 receptor activation has also been shown to signal caspase-1 and IL-1β/IL-18 independent release of cathepsins [111,112], PGE 2 [8], phosphatidylserine [113], and MMP-9 [114], all of which are implicated in cellular processes that play a defined role in inflammation. ATP is also reported to act as a long-range "find me" signal (chemoattractant) to recruit monocytes and macrophages [115].…”

The P2X7-nonmuscle myosin membrane complex regulates phagocytosis of nonopsonized particles and bacteria by a pathway attenuated by extracellular ATP

“…Cellular K ϩ depletion is thought to be a costimulus for formation of the inflammasome 16,17 and secretion of proinflammatory cytokines interleukin-1␤ (IL-1␤) and IL-18. 18,19 Other downstream effects of P2X 7 activation include blebbing of the plasma membrane, 20 shedding of surface L-selectin and CD23, 21 rapid secretion of matrix metalloproteinase-9, 22 and activation of the caspase cascade leading to a form of apoptotic cell death. 23,24 The role of P2X 7 as a proinflammatory receptor is supported by results from the P2X 7 gene-deleted mouse, which shows major reduction in inflammatory responses to various noxious stimuli.…”