Histamine suppresses gene expression and synthesis of tumor necrosis factor α via histamine H2 receptors

Abstract

Histamine and tumor necrosis factor a (TNF-α) can each contribute to the pathogenesis of allergic reactions and chronic inflammatory diseases. We now report the effect of histamine on gene expression and total cellular synthesis of TNF-α. Lipopolysaccharide (LPS)-induced synthesis of TNF-α in peripheral blood mononuclear cells (PBMC) from 18 healthy donors was suppressed by histamine concentrations from 10-6 to 10-4 M, levels comparable with those measured in tissues after mast cell degranulation. Histamine (10-5 M) markedly suppressed LPS-induced synthesis of TNF-α in both unfractionated PBMC (83% inhibition, p < 0.001) and monocytes purified by positive selection of LeuM3+ cells (62% inhibition, p < 0.05). The suppressive effect of histamine on TNF-α synthesis did not require the presence of T cells. The histamine-mediated decrease in TNF-α synthesis was not affected by indomethacin, nor by diphenhydramine, an H1 receptor antagonist, but was reversed by cimetidine or ranitidine, H2 receptor antagonists, in a dose-dependent manner. Suppression of TNF-α synthesis by histamine is likely to be a transcriptional event, since histamine (10-5 M) reduced TNF-α mRNA levels fourfold. These results suggest that histamine release from mast cells may paradoxically limit the extent of inflammatory and immune reactions by suppressing local cytokine synthesis in H2 receptor-bearing cells.