SUPPRESSION OF T-CELL-MEDIATED INJURY IN HUMAN GUT BY INTERLEUKIN-10 - ROLE OF MATRIX METALLOPROTEINASES

Background & Aims: Activation of lamina propria T cells with pokeweed mitogen in human fetal gut explant cultures results in severe mucosal injury. In the same system, Staphylococcus aureus enterotoxin B produc es villus atrophy and crypt cell hyperplasia. The aim of this study wa s to examine the ability of interleukin (IL)-10 to modify these change s. Methods: Mucosal pathology and lamina propria glycosaminoglycans we re assessed histologically, and CD3(+), CD25(+) and alpha-actin smooth muscle-positive cells were determined by immunohistochemistry, Revers e plaque assays and quantitative reverse-transcriptase polymerase chai n reaction were used to analyze the cytokine response. Matrix metallop roteinase production was analyzed by Western blotting, in situ hybridi zation, and zymography, Results: Both experimental enteropathies produ ced mucosal damage, although injury was greater after pokeweed mitogen activation than S. aureus enterotoxin B, In both cases, the increase in cytokine-secreting cells and transcripts observed after T-cell acti vation was inhibited by IL-10. IL-10 also inhibited the increase in co llagenase and stromelysin-l in the explant culture supernatants and th e loss of glycosaminoglycans. IL-10 decreased metalloproteinase produc tion in control explants and increased matrix. In mesenchymal cells, I L-10 had a minor effect on metalloproteinase production, Conclusions: IL-10 downregulates mucosal T-cell activation, metalloproteinase produ ction, and loss of extracellular matrix and prevents mucosal damage in the gut.