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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1004612

Received for publication October 22, 2004.
Revised February 8, 2005.
Accepted for publication February 23, 2005.

Article

Regulation of matrix metalloproteinase-9 release from IL-8-stimulated human neutrophils

Subhadeep Chakrabarti * and Kamala D. Patel *{dagger}@

Departments of *Physiology and Biophysics and {dagger}Biochemistry and Molecular Biology, Immunology Research Group, University of Calgary, Alberta, Canada

@ To whom correspondence should be addressed. E-mail: kpatel{at}ucalgary.ca.


  Abstract

Matrix metalloproteinase-9 (MMP-9) is present in the tertiary granules of neutrophils and can be released following stimulation. We examined the signaling mechanisms that regulate interleukin-8 (IL-8)-mediated MMP-9 release from neutrophils. IL-8 activates neutrophils by interacting with two receptors: CXC chemokine receptor 1 (CXCR1) and CXCR2. Blocking CXCR1 had no effect on IL-8-mediated MMP-9 release, whereas blocking CXCR2 significantly reduced MMP-9 release. We also found that stimulating CXCR2 alone was sufficient to induce MMP-9 release. This process was independent of changes in the intracellular calcium concentration. Src-family kinases and protein kinase C (PKC) were involved in two mutually exclusive pathways regulating IL-8-mediated MMP-9 release. Inhibition of extracellular signal-regulated kinase (ERK)1/2 blocked IL-8-mediated MMP-9 release; however, inhibition of p38 mitogen-activated protein kinase had no effect on MMP-9 release. We found ERK1/2 was activated downstream of PKC but not Src-family kinases in this system. These data suggest that IL-8-induced MMP-9 release from neutrophils is mediated through CXCR2 and involves two distinct pathways, one involving PKC and ERK1/2 and the other involving Src-family kinases. Furthermore, our data show that the mechanisms that regulate MMP-9 release from tertiary granules are different from those that regulate primary granule release.

Key Words: signal transduction • tissue remodeling • chemokines • inflammation




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