C5a mediates secretion and activation of matrix metalloproteinase 9 from human eosinophils and neutrophils

Richard G. DiScipio, Ingrid U. Schraufstatter, Lyudmila Sikora, Bruce L. Zuraw, P. Sriramarao

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Matrix metalloproteinase 9 (MMP-9) is a crucial proteinase, utilized by both eosinophils and neutrophils, that mediates transmigration through extracellular basement membranes. We have found that neutralization of MMP-9 by a monoclonal antibody or a chemical inhibitor blocked C5a dependent chemotaxis of these granulocytes in vitro. The levels of MMP-9 secreted by the action of C5a from eosinophils were about 50-fold lower than those from neutrophils, consistent with results from confocal microscopy, where the density of MMP-9 containing granules was fewer within eosinophils than in neutrophils. Zymography indicated gelatin degrading activity of the molecular size of proMMP-9 in supernatants from eosinophils and neutrophils stimulated by C5a, with no evidence of proteolytic activation. Instead MMP-9 activation appeared oxidative, since inhibition of NADPH oxidase and nitric oxide synthase by DPI or L-NIL abrogated C5a-mediated chemotaxis through basement membranes. In keeping with this mode of activation, C5a, known as an agent of superoxide generation, was also found to induce secretion of nitric oxide from human eosinophils and rat granulocytes and monocytes. In conclusion C5a is an important mediator that brings about secretion and oxidative activation of MMP-9, a requisite protease for transmigration, from both eosinophils and neutrophils.

Original languageEnglish (US)
Pages (from-to)1109-1118
Number of pages10
JournalInternational Immunopharmacology
Volume6
Issue number7
DOIs
StatePublished - Jul 2006

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health: RO1 HL 55657 to IUS; PO1 AI50498 to BLZ (GCRC grant RR00837); RO1 AI 35796, RO1 HL079304, and TRDRP-10RT to PS.

Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.

Keywords

  • C5a
  • Chemotaxis
  • Eosinophils
  • Gelatinase B
  • Neutrophils

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