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| A major role for matrix metalloproteinases in T cell injury in the gut |
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| Author(s): Pender SLF, Tickle SP, Docherty AJP, Howie D, Wathen NC, MacDonald TT |
| Source: JOURNAL OF IMMUNOLOGY Volume: 158 Issue: 4 Pages: 1582-1590 Published: FEB 15 1997 |
| Times Cited: 215 References: 69 |
| 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-1 beta 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Pender, SLF (reprint author), ST BARTHOLOMEWS & ROYAL LONDON SCH MED & DENT, DEPT PEDIAT GASTROENTEROL, LONDON EC1A 7BE, ENGLAND |
Addresses:
1. ST BARTHOLOMEWS & ROYAL LONDON SCH MED & DENT, JOINT ACAD DEPT OBSTET & GYNECOL, LONDON, ENGLAND
2. CELLTECH LTD, SLOUGH SL1 4EN, BERKS ENGLAND |
| Publisher: AMER ASSOC IMMUNOLOGISTS, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 |
| Subject Category: Immunology |
| IDS Number: WG304 |
| ISSN: 0022-1767 |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |