Regulation of cytokine production by histamine through H₂-receptor stimulation

Histamine is a well known mediator of inflammation including the allergic reaction. Histamine has been suggested to be a immunomodulator. Recent studies revealed that induction of histidine decarboxylase occurs by the stimulation of several cytokines and LPS, suggesting an immunomodulatory role of the inducible histamine. Using human PBMC culture, it was demonstrated that histamine was a potent inducer of IL-18, IFN-γ in human PBMC. Histamine did not induce the production of IL-12. The effects of histamine on cytokine production were mimicked by H₂-selective agonists and inhibited by H₂- but not by H₁- and H₃-antagonists, indicating the involvement of H₂-receptors in histamine action. All effects of histamine were abolished by the presence of anti-IL-18 antibody or IL-1b-converting enzyme/caspase-1 inhibitor, indicating that histamine action is dependent on mature IL-18 secretion and that IL-18 production was present most upstream of the cytokine cascade triggered by histamine. Histamine is a very important modulator of Th1 cytokine production in PBMC and is quite unique in triggering the cytokine cascade without inducing IL-12 production.