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Published online before print November 7, 2005
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,1
* Departments of Physiology and Biophysics and
Biochemistry and Molecular Biology, Immunology Research Group, University of Calgary, Alberta, Canada
1 Correspondence: Departments of Physiology and Biophysics and Biochemistry and Molecular Biology, Immunology Research Group, University of Calgary, 3330 Hospital Dr., N.W., Calgary, Alberta T2N 4N1, Canada. E-mail: kpatel{at}ucalgary.ca
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 ß2-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 ß2-integrin-mediated adhesion. Similarly, blocking Src family kinases with the inhibitor PP2 only attenuated TNF-induced MMP-9 release. Blocking ß2-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 
and PKC 
in maximal MMP-9 release. These data suggest that MMP-9 release from tertiary granules uses ß2-integrin-independent signaling pathways. Furthermore, PKC isoforms play a critical role in regulating tertiary granule release.
Key Words: degranulation • signal transduction • integrins • protein kinase C • inflammation
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