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A major role for matrix metalloproteinases in T cell injury in the gut.

S L Pender, S P Tickle, A J Docherty, D Howie, N C Wathen and T T MacDonald
J Immunol February 15, 1997, 158 (4) 1582-1590;
S L Pender
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S P Tickle
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A J Docherty
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D Howie
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N C Wathen
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T T MacDonald
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Abstract

Activated lamina propria T cells responding to luminal Ags are thought to be important in celiac disease and Crohn's disease, and T cells responding to foreign MHC products are also important in intestinal graft-vs-host disease and intestinal transplant rejection. However, the mechanism(s) by which T cells mediate damage in the gut is not known. We have previously shown that activation of lamina propria T cells by PWM in explant cultures of second trimester human small intestine produces severe tissue injury, with epithelial cell shedding and loss of villi. In this study, we have investigated the role of matrix metalloproteinases in this system. Organ culture supernatants of explants stimulated with PWM showed a 3-fold increase in the concentration of interstitial collagenase and a 10-fold increase in stromelysin-1 compared with control explant culture supernatants. Tissue inhibitors of metalloproteinase-1 and -2 concentrations were unchanged. Increased metalloproteinase enzymatic activity was detected by gelatin and casein zymography. Western blotting revealed the active forms of interstitial collagenase and stromelysin-1 in PWM-stimulated culture supernatants. Up-regulation of mRNA for interstitial collagenase, stromelysin-1, and gelatinase-B was also seen. Nanomolar amounts of recombinant stromelysin-1 added directly to explants produced rapid severe tissue injury. PWM-induced mucosal injury was inhibited by a synthetic peptidomimetic inhibitor of matrix metalloproteinases. Mesenchymal cells isolated from the mucosa of human fetal small intestine produced increased amounts of interstitial collagenase, gelatinase A, and stromelysin-1 when stimulated with IL-1beta or TNF-alpha. These results suggest that T cell activation in the lamina propria results in increased production of matrix metalloproteinases, which by degrading the lamina propria matrix represent a major pathway by which T cells cause injury in the gut.

  • Copyright © 1997 by American Association of Immunologists

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The Journal of Immunology
Vol. 158, Issue 4
15 Feb 1997
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A major role for matrix metalloproteinases in T cell injury in the gut.
S L Pender, S P Tickle, A J Docherty, D Howie, N C Wathen, T T MacDonald
The Journal of Immunology February 15, 1997, 158 (4) 1582-1590;

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A major role for matrix metalloproteinases in T cell injury in the gut.
S L Pender, S P Tickle, A J Docherty, D Howie, N C Wathen, T T MacDonald
The Journal of Immunology February 15, 1997, 158 (4) 1582-1590;
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Print ISSN 0022-1767        Online ISSN 1550-6606