Inducible histamine protects mice from P.acnes-primed and LPS-induced hepatitis through H2-receptor stimulation

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Inducible histamine and histamine H2-receptors have been suggested to be involved in innate immune response. We examined a functional role of inducible histamine in the protection against hepatic injury and lethality in Propionibacterium acnes-primed and lipopolysaccharide-induced hepatitis, using wistidine decarboxylase knockout and H2-receptor knockout mice. Lipopolysaccharide challenge after Propionibacterium acnes-priming increased histidine decar boxylase activity in the liver of wild-type mice, associated with a marked elevation of histamine turnover. Histidine decarboxylase-like immunoreactivity was observed in CD68-positive Kupffer cells/macrophages. Treatment of wild-type mice with famotidine or ranitidine but not d-chlorpheniramine augmented hepatic injury and inhibited the survival rate significantly. The same dose of Propionibacterium acnes and lipopolysaccharide induced severe hepatitis and high lethality in histidine decarboxylase knockout and H2-receptor knockout mice, the former were rescued by the subcutaneous injection of histamine. Immunohistochemical study supported the protective role of histamine against the apoptosis of hepatocytes. Histamine suppressed the expression of IL-18 and tumor necrosis factor-α in the liver, leading to the reduced plasma levels of cytokines including IL-18,TNF-α,IL-12,IFN-γ and IL-6. These findings as a whole indicated that endogenously produced histamine in Kupffer cells/macrophages plays a very important role in preventing excessive innate immune response in endotoxin-induced fulminant hepatitis through the stimulation of H2-receptors.