Enhancing lamina propria Th1 cell responses with interleukin 12 produces severe tissue injury

Background & Aims: Interleukin (IL)-12 is believed to modulate local T-cell response in human colitis. A direct functional relationship between IL-12 and tissue injury in human intestine has not been reported. The aim of this study was to examine changes that take place in explant cultures of human fetal gut after stimulation of T cells with anti-CD3 in the presence of exo genous IL-12/IL-18. Methods: T cells in explants of fetal gut were activate d with anti-CD3 antibody and/or IL-12 or IL-18. Mucosal pathology was deter mined by immunohistochemistry. Quantitative reverse-transcription polymeras e chain reaction (RT-PCR) and enzyme-linked immunosorbent assay were used t o determine cytokine synthesis, and the production of matrix metalloprotein ases was analyzed by RT-PCR and Western blotting. Results: Activation of T cells in explants with anti-CD3 antibody elicited very little interferon (I FN)-gamma and tumor necrosis factor (TNF)-alpha production and no tissue in jury. Addition of graded doses of IL-12 with anti-CD3 resulted in a signifi cant increase in both IFN-gamma and TNF-alpha. This change was associated w ith a massive increase in stromelysin-1 expression and severe tissue injury , which was inhibitable by a stromelysin-1 inhibitor. Costimulation of expl ants with anti-CD3 and IL-18 induced only IFN-gamma and no tissue injury. C onclusions: IL-12 can convert a physiological T-cell signal into a strong s ignal with the downstream effect of elevating tissue stromelysin-1 concentr ation and mucosal degradation.