TITLE

FIBROBLAST-DERIVED MATRIX METALLOPROTEINASES ACTIVATE A POTENT NEUTROPHIL CHEMOATTRACTANT FROM INTESTINAL EPITHELIAL CELLS

AUTHOR(S)
Kruidenier, L.; MacDonald, T.T.; Sanderson, I.R.
PUB. DATE
April 2003
SOURCE
Gut;Apr2003 Supplement 1, Vol. 52, pA57
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
The upregulation of matrix metalloproteinases (MMPs) in the inflamed gut has mainly been associated with mucosal degradation and ulceration. However, their in vitro capacity to specifically cleave inflammatory mediators indicates that MMPs may also have a profound immunoregulatory impact. In this study, we assessed whether MMPs proteolytically modify intestinal epithelial chemokine signalling. Fully differentiated CaCo-2 cells were grown on filters, stimulated with lL-1β, and exposed basolaterally to nanomolar concentrations of activated MMP-3. Chemotaxis assays of the conditioned media revealed that MMP-3 dosedependently induced the neutrophil, but not monocyte, chemoattractant capacity of CaCo-2 cells. A similar response was obtained when these cells were co-cultured with IL-1β-stimulated colonic fibroblasts (CCD-18co), which expressed various MMPs, including MMP-3, -10, and -12. The addition of doxycyclin, a broad-spectrum MMP inhibitor, disrupted the CaCo-2 chemotactic response. The principal mediator of these protease-related effects was identified as the potent neutrophil chemokine neutrophil activating peptide 2 (NAP-2, CXCL7), a cleavage product of biologically inactive platelet basic protein (PBP). Antibodies against NAP-2 greatly inhibited the MMP-induced chemotactic response, and PBP mRNA and protein was detected in stimulated CaCo-2, but not in CCD-18co cells. Our data suggest that fibroblast-derived MMPs proteolytically activate the neutrophil chemokine NAP-2 from the intestinal epithelium, adding a novel dimension to MMP function and to our understanding of the pathogenesis of intestinal inflammation.
ACCESSION #
9747670

 

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