Myofibroblast matrix metalloproteinases activate the neutrophil chemoattractant CXCL7 from intestinal epithelial cells
Myofibroblast matrix metalloproteinases activate the neutrophil chemoattractant CXCL7 from intestinal epithelial cells
Background & Aims: The up-regulation 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 have a profound immunoregulatory impact. We hypothesized that MMPs proteolytically modify intestinal epithelial chemokine signaling.
Methods: Interleukin-1?–stimulated Caco-2 cells were exposed basolaterally to nanomolar concentrations of activated MMP-3 or cocultured with interleukin-1?–stimulated, MMP-producing, colonic myofibroblasts (CCD-18co). The conditioned media were subjected to chemotaxis assays. In addition, epithelial cells from patients with colitis were examined by real-time polymerase chain reaction, immunoblotting, and immunohistochemistry.
Results: MMP-3 dose-dependently induced the neutrophil (up to 5-fold) but not monocyte chemoattractant capacity of Caco-2 cells. A similar Caco-2 chemotactic response was obtained in the Caco-2/CCD-18co cocultures. The principal mediator of these protease-related effects was identified as the potent neutrophil chemokine CXCL7 (neutrophil activating peptide 2), a proteolytic cleavage product of chemotactically inert platelet basic protein (PBP), not previously identified in the intestine. Antibodies against CXCL7 inhibited the MMP-induced chemotactic response by 84%, and PBP mRNA and protein were detected in stimulated Caco-2 but not in CCD-18co cells. Furthermore, PBP transcript and protein levels were low in the mucosa and in isolated epithelial cells from patients with Crohn’s disease and from normal intestine but increased up to 13-fold in patients with ulcerative colitis.
Conclusions: These findings identify a novel proinflammatory action of MMPs in inflammation and suggest that lamina propria myofibroblasts are required to achieve maximal intestinal epithelial immune activation.
Abbreviations used in this paper: ENA-78, CXCL 5; GRO, growth-related oncogene; IL, interleukin; MCP, monocyte chemoattractant protein; MMP, matrix metalloproteinase; NAP-2, neutrophil-activating peptide 2; PBP, platelet basic protein
127-136
Kruidenier, L.
02498cb9-6dad-43f6-bb2f-a35da932b1a5
MacDonald, T.T.
171334aa-638a-42b0-99f6-e860e2f0ca45
Collins, J.E.
be0e66f1-3036-47fa-9d7e-914c48710ba4
Pender, S.L.
62528b03-ec42-41bb-80fe-48454c2c5242
Sanderson, I.R.
dd5e248c-c699-4f27-b122-9f4a9aa13595
January 2006
Kruidenier, L.
02498cb9-6dad-43f6-bb2f-a35da932b1a5
MacDonald, T.T.
171334aa-638a-42b0-99f6-e860e2f0ca45
Collins, J.E.
be0e66f1-3036-47fa-9d7e-914c48710ba4
Pender, S.L.
62528b03-ec42-41bb-80fe-48454c2c5242
Sanderson, I.R.
dd5e248c-c699-4f27-b122-9f4a9aa13595
Kruidenier, L., MacDonald, T.T., Collins, J.E., Pender, S.L. and Sanderson, I.R.
(2006)
Myofibroblast matrix metalloproteinases activate the neutrophil chemoattractant CXCL7 from intestinal epithelial cells.
Gastroenterology, 130 (1), .
(doi:10.1053/j.gastro.2005.09.032).
(PMID:16401476)
Abstract
Background & Aims: The up-regulation 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 have a profound immunoregulatory impact. We hypothesized that MMPs proteolytically modify intestinal epithelial chemokine signaling.
Methods: Interleukin-1?–stimulated Caco-2 cells were exposed basolaterally to nanomolar concentrations of activated MMP-3 or cocultured with interleukin-1?–stimulated, MMP-producing, colonic myofibroblasts (CCD-18co). The conditioned media were subjected to chemotaxis assays. In addition, epithelial cells from patients with colitis were examined by real-time polymerase chain reaction, immunoblotting, and immunohistochemistry.
Results: MMP-3 dose-dependently induced the neutrophil (up to 5-fold) but not monocyte chemoattractant capacity of Caco-2 cells. A similar Caco-2 chemotactic response was obtained in the Caco-2/CCD-18co cocultures. The principal mediator of these protease-related effects was identified as the potent neutrophil chemokine CXCL7 (neutrophil activating peptide 2), a proteolytic cleavage product of chemotactically inert platelet basic protein (PBP), not previously identified in the intestine. Antibodies against CXCL7 inhibited the MMP-induced chemotactic response by 84%, and PBP mRNA and protein were detected in stimulated Caco-2 but not in CCD-18co cells. Furthermore, PBP transcript and protein levels were low in the mucosa and in isolated epithelial cells from patients with Crohn’s disease and from normal intestine but increased up to 13-fold in patients with ulcerative colitis.
Conclusions: These findings identify a novel proinflammatory action of MMPs in inflammation and suggest that lamina propria myofibroblasts are required to achieve maximal intestinal epithelial immune activation.
Abbreviations used in this paper: ENA-78, CXCL 5; GRO, growth-related oncogene; IL, interleukin; MCP, monocyte chemoattractant protein; MMP, matrix metalloproteinase; NAP-2, neutrophil-activating peptide 2; PBP, platelet basic protein
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Published date: January 2006
Additional Information:
Basic–alimentary tract
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Local EPrints ID: 27214
URI: http://eprints.soton.ac.uk/id/eprint/27214
ISSN: 0016-5085
PURE UUID: c1e471c4-2291-47af-a049-5aa2e4602ffe
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Date deposited: 27 Apr 2006
Last modified: 16 Mar 2024 03:19
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Author:
L. Kruidenier
Author:
T.T. MacDonald
Author:
I.R. Sanderson
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