title: Regulation of matrix metalloproteinase-9 (MMP-9) in TNF-stimulated neutrophils: novel pathways for tertiary granule release.
abstract: Matrix metalloproteinase-9 (MMP-9) is present in the tertiary granules of neutrophils and is rapidly released following stimulation. We examined the pathways that regulate tumor necrosis factor (TNF)-mediated MMP-9 release and found this to be dependent on the TNF receptor I. TNF rapidly activated extracellular signal-regulated kinase and p38 mitogen-activated protein kinases, but neither of these pathways was critical for MMP-9 release. Many neutrophil responses to TNF require beta2-integrin-dependent signaling and subsequent Src family kinase activation. In contrast, we found that MMP-9 release from tertiary granules was only partially affected by blocking beta2-integrin-mediated adhesion. Similarly, blocking Src family kinases with the inhibitor PP2 only attenuated TNF-induced MMP-9 release. Blocking beta2-integrin-mediated adhesion and Src family kinases did not result in additive inhibition of MMP-9 release. In contrast, inhibiting protein kinase C (PKC) with a pan-specific inhibitor blocked greater than 85% of MMP-9 release. Inhibitors against specific PKC isoforms suggested a role for PKC alpha and PKC delta in maximal MMP-9 release. These data suggest that MMP-9 release from tertiary granules uses beta2-integrin-independent signaling pathways. Furthermore, PKC isoforms play a critical role in regulating tertiary granule release.
authors.affiliation: Department of Physiology and Biophysics, Immunology Research Group, University of Calgary, Alberta, Canada.
authors.forename: Subhadeep
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Zee
authors.forename: Kamala D
authors.initials: KD
authors.lastname: Patel
mesh_terms: D018821:CD18 Antigens / Q000276:immunology; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D018375:Neutrophil Activation / Q000187:drug effects* / Q000276:immunology; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000276:immunology; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000276:immunology; D022142:Secretory Vesicles / Q000201:enzymology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology; D019061:src-Family Kinases / Q000276:immunology
chemical_list: D018821:CD18 Antigens; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019061:src-Family Kinases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9