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

Record type: Article

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.

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Citation

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

More information

Published date: 15 February 1997

Identifiers

Local EPrints ID: 76236
URI: http://eprints.soton.ac.uk/id/eprint/76236
ISSN: 0022-1767
PURE UUID: 137176cf-d92b-4066-a8bf-8aa8b77ba677
ORCID for S.L. Pender: ORCID iD orcid.org/0000-0001-6332-0333

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Date deposited: 11 Mar 2010
Last modified: 18 Jul 2017 23:41

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Contributors

Author: S.L. Pender ORCID iD
Author: S.P. Tickle
Author: A.J. Docherty
Author: D. Howie
Author: N.C. Wathen
Author: T.T. MacDonald

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