Histamine and tumor necrosis factor alpha (TNF-alpha) 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-alpha. Lipopolysaccharide (LPS)-induced synthesis of TNF-alpha 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-alpha in both unfractionated PBMC (83% inhibition, p less than 0.001) and monocytes purified by positive selection of LeuM3+ cells (62% inhibition, p less than 0.05). The suppressive effect of histamine on TNF-alpha synthesis did not require the presence of T cells. The histamine-mediated decrease in TNF-alpha 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-alpha synthesis by histamine is likely to be a transcriptional event, since histamine (10(-5) M) reduced TNF-alpha 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.