Substance P regulates Th1-type colitis in IL-10 knockout mice.

Substance P (SP) is a proinflammatory molecule that interacts with a neurokinin 1 receptor (NK-1R), which is on T cells and helps control IFN-gamma production. IL-10(-/-) mice given a nonsteroidal anti-inflammatory drug (NSAID) develop Th1 colitis. We studied the importance of SP and NK-1R in this colitis model. LP T cells were isolated to study their NK-1R expression. LP T cells from IL-10(-/-) mice expressed NK-1R and produced IFN-gamma only after NSAID treatment and induction of colitis. LP T cells from NSAID-treated wild-type controls or from age-matched untreated IL-10(-/-) animals did not express NK-1R or produce IFN-gamma. Experiments showed that IL-12 induced NK-1R transcription in CD4(+) T cells cultured in vitro. However, T cells cultured with IL-12 and IL-10 did not express NK-1R. IL-10 also down-modulated ongoing NK-1R expression. Mice given NK-1R antagonist after NSAID induction of severe colitis showed nearly complete reversal of inflammation, and LP T cells ceased IFN-gamma secretion. Thus, intestinal inflammation in IL-10(-/-) mice is associated with the appearance of NK-1R in mucosal T cells, and an interplay between IL-12 and IL-10 regulates T cell NK-1R transcription. NK-1R antagonist reverses ongoing intestinal inflammation attesting to the importance of SP and its receptor in mucosal inflammation.