HISTAMINE ENHANCES INTERLEUKIN (IL)-1-INDUCED IL-1 GENE-EXPRESSION AND PROTEIN-SYNTHESIS VIA H-2 RECEPTORS IN PERIPHERAL-BLOOD MONONUCLEAR-CELLS - COMPARISON WITH IL-1 RECEPTOR ANTAGONIST

Histamine and IL-1 have been implicated in the pathogenesis of chronic inflammatory diseases, such as pulmonary allergic reactions and rheumatoid arthritis. We therefore investigated whether histamine modulated the synthesis of IL-1beta. Human PBMC were stimulated with IL-1alpha (10 ng/ml) in the absence or presence of histamine (10(-9)-10(-4) M). Histamine alone did not induce protein synthesis or mRNA accumulation for IL-1beta. IL-1alpha-induced IL-1beta synthesis was enhanced two to threefold by histamine concentrations from 10(-6)-10(-4) M. Cimetidine, an H-2 receptor antagonist, reversed the histamine (10(-5) M)-mediated increase in IL-1alpha-induced synthesis. Diphenhydramine, an H-1 receptor antagonist, had no effect. Indomethacin, a cyclooxygenase inhibitor, significantly reduced IL-1alpha-induced IL-1beta synthesis, but had no effect on the histamine-mediated increase in IL-1alpha-induced IL-1beta synthesis. Histamine (10(-5) M) enhanced and sustained IL-1beta mRNA levels in IL-1alpha-stimulated PBMC. However, histamine reduced IL-1beta mRNA half-life (2.4 vs 1.2 h), suggesting that histamine enhances IL-1alpha-induced IL-1beta synthesis at the level of transcriptional activation. On the other hand, histamine (10(-5) M) did not affect IL-1alpha-induced synthesis of IL-1 receptor antagonist. These results suggest that mast cells may sustain chronic inflammatory processes by upregulating self-induction of IL-1 through histamine release.