Substance P and the regulation of inflammation in infections and inflammatory bowel disease.

Substance P (SP) and its natural analogue hemokinin-1 (HK1) are produced by lymphocytes and macrophages, and at times B cells. These peptides are an important component of the immune response during several infections and in inflammatory bowel disease (IBD). The synthesis of SP and HK1 in leucocytes is subject to immune regulation. IL12 and IL23 stimulate T cells and macrophages to make SP respectively. The cytokines driving HK1 production are not presently defined. These peptides act through a shared receptor called neurokinin-1. T cells, macrophages and probably other immune cell types can express this receptor. Several cytokines IL12, IL18 and TNFα as well as T-cell antigen receptor activation induce neurokinin-1 receptor expression on T cells, while IL10 blocks receptor display. TGFβ delays internalization of the SP/neurokine-1R complex on T cells resulting in stronger receptor signalling. One of the functions of SP and neurokinin-1 receptor is to enhance T cell IFNγ and IL17 production, amplifying the proinflammatory response. Thus, SP and HK1 have overlapping functions and are part of a sophisticated immune regulatory circuit aimed at amplifying inflammation at mucosal surfaces and in other regions of the body as shown in animal models of infection and IBD.