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The Journal of Immunology, 2003, 171: 3762-3767.
Copyright © 2003 by The American Association of Immunologists

Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice1

Joel V. Weinstock2,*, Arthur Blum*, Ahmed Metwali*, David Elliott, Nigel Bunnett{dagger} and Razvan Arsenescu*

* Division of Gastroenterology-Hepatology, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242; and {dagger} Department of Surgery and Physiology, University of California, San Francisco, CA

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.




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