Vol. 300, Issue 1, 227-235, January 2002

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

Hideo Kohka Takahashi , Atsushi Yoshida, Hiromi Iwagaki, Tadashi Yoshino, Hideyuki Itoh, Toshihiko Morichika, Minori Yokoyama, Tadaatsu Akagi, Noriaki Tanaka, Shuji Mori and Masahiro Nishibori

Departments of Pharmacology (H.K.T., M.Y., S.M., M.N.), Tumour Biology (H.K.T., A.Y., H.I., T.M., N.T.), and Pathology (T.Y., T.A.), Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

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- (IFN-), and tumor necrosis factor- (TNF-) 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-, and TNF- 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- 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.