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.
D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D004195:Disease Models, Animal; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics* / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064729:Neurokinin-1 Receptor Antagonists; D010894:Piroxicam / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis / Q000235:genetics; D013373:Substance P / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
D064729:Neurokinin-1 Receptor Antagonists; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D016753:Interleukin-10; D010894:Piroxicam; D018664:Interleukin-12; D013373:Substance P