Histamine regulation of interleukin-18-initiating cytokine cascade is associated with down-regulation of intercellular adhesion molecule-1 expression in human peripheral blood mononuclear cells

In the previous study, we demonstrated that interleukin (IL)-18 up-regulated intercellular adhesion molecule-1 (ICAM-1) expression on monocytes in human peripheral blood mononuclear cells (PBMC) and that heterotypic interaction between monocytes/T or NK cells through ICAM-1/LFA-1 intensified the production of IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) in PBMC. In the present study, we demonstrate that histamine inhibited the ICAM-1 expression in monocytes induced by IL-18 using flow cytometry and that the responses of IL-12, IFN-γ, and TNF-α induced by IL-18 were concentration dependently inhibited by coexisting histamine, whereas IL-18-inhibited IL-10 production was reversed by the same concentrations of histamine. The modulatory effects of histamine on ICAM-1 expression and cytokine production were all concentration dependently antagonized by famotidine but not by d-chlorpheniramine and thioperamide, and were mimicked by selective H₂-receptor agonists but not by H₁- and H₃-receptor agonists, indicating the involvement of H₂-receptors in histamine action. The inhibition of IL-18-induced IFN-γ by histamine was ascribed to the strong inhibition of IL-12 production by histamine. Histamine thus operates the negative feedback mechanism against IL-18-activated cytokine cascade through the strong inhibitory effect on ICAM-1 expression and IL-12 production in monocytes, contributing to the formation of diverse pattern of cytokine activation from Th1 to Th2, depending on the monocyte/macrophage activation and cytokine environment.