Cytokine responses of intraepithelial lymphocytes are regulated by histamine H2 receptor

Histamine participates in the immune regulation of several gastrointestinal diseases. However, the effect of histamine on intestinal intraepithelial lymphocytes (IELs), the front line of the intestinal mucosal immune system, is not well understood. We examined whether histamine has a direct effect on cytokine production by IELs and the involvement of histamine receptor subtypes. Murine IELs were activated by PMA plus ionomycin with/without histamine. Secreted cytokines were measured and compared with those of splenocytes. Intracellular cytokines were detected by flow cytometry. Expression of histamine receptor subtypes in IELs was examined by RT-PCR. Histamine H-1 receptor (H1R), H2R, and H4R, but not H3R mRNA were expressed on IELs. Histamine significantly decreased Th1-cytokine (IFN-gamma, TNF-alpha, and IL-2) and also IL-4 production in IELs as well as splenocytes. The selective H2R antagonist famotidine, but not the H1R antagonist pyrilamine nor the H3R/H4R antagonist thioperamide, competes with the inhibitory effect of histamine on these cytokine production in IELs. These suppressive effects of histamine were mimicked by a selective H2R/H4R agonist dimaprit. Further, these suppressive effects of histamine for Th1-cytokine and IL-4 did not accompany the enhancement of IL-10 production or IL-10 mRNA level in IELs. Intracellular cytokine analysis revealed that the number of IFN-gamma-producing alpha beta T cells was significantly reduced by histamine in IELs. Histamine has a direct suppressive effect on IEL-derived cytokines via H2R, which would have a crucial role in the suppression of local immunoregulation in the intestinal epithelium.