To study the potential interaction between cytokine and serotonin (5-HT) signal transduction, we evaluated the effect of interleukin-1 beta (IL-1 beta) on the 5-HT2 receptor-mediated mobilization of intracellular Ca2+ in cultured rat C6BU-1 glioma cells. Pretreatment of cells with IL-1 beta significantly inhibited the 5-HT-induced mobilization of Ca2+ in a dose (30-1000 U/ml)- and time (12-24 h)-dependent manner. Inhibition was observed when cells were stimulated with concentrations of 5-HT of > or = 1 microM, which induced the maximal 5-HT response. Lipopolysaccharide (1 microgram/ml) also inhibited 5-HT-induced Ca2+ mobilization, but heat-inactivated IL-1 beta as well as interferon-alpha (1000 U/ml), interferon-gamma (1000 U/ml), and tumor necrosis factor-alpha (2000 U/ml) did not. The inhibitory effects of IL-1 beta and LPS were significantly prevented by genistein, a selective tyrosine kinase antagonist, and by H7, a potent inhibitor of protein kinase C. These results indicate that IL-1 beta and LPS inhibit 5-HT2 receptor-mediated Ca2+ mobilization via pathways that include the activation of a tyrosine kinase and protein kinase C. The interaction between cytokines (IL-1 beta) and monoamines (5-HT) may serve to modulate signal transduction in the central nervous system.