Histamine Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production in an Intercellular Adhesion Molecule-1- and B7.1-Dependent Manner

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Abstract
Lipopolysaccharide (LPS) is recognized as a key molecule in the pathogenesis of Gram negative sepsis and septic shock. In the present study, we demonstrate that LPS (1–1000 pg/ml) concentration dependently up-regulated the expression of intercellular adhesion molecule (ICAM)-1, B7.1, and B7.2 on human monocytes using fluorescence-activated cell sorting analysis, and that tumor necrosis factor (TNF)-α production induced by LPS in peripheral blood mononuclear cells (PBMCs) was inhibited by the addition of antibodies against these adhesion molecules, suggesting the dependence of TNF-α production on cell-cell interaction through these adhesion molecules. Moreover, we found that histamine (10−7–10−4M) concentration dependently inhibited the expression of ICAM-1 and B7.1, but not B7.2 on monocytes induced by LPS. Histamine also inhibited the responses of TNF-α production induced by LPS. The modulatory effects of histamine on ICAM-1 and B7.1 expression and TNF-α 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-, H3-, and H4-receptor agonists, indicating the involvement of H2-receptors in the histamine action. Dibutyryl cAMP down-regulated ICAM-1 and B7.1 expression on monocytes stimulated by LPS, suggesting the mediation by the cyclic adenosine monophosphate-protein kinase A pathway of H2-receptor activation. These results as a whole indicated that histamine via H2-receptor inhibited the LPS-induced TNF-α production through the regulation of ICAM-1 and B7.1 expression, leading to the reduction of innate immune response stimulated by LPS.