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

Minori Yokoyama, Akira Yokoyama, Shuji Mori, Hideo K. Takahashi, Tadashi Yoshino, Takeshi Watanabe, Takehiko Watanabe, Hiroshi Ohtsu, Masahiro Nishibori

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


Background & Aims: Inducible histamine and histamine H2-receptors have been suggested to be involved in innate immune response. Methods: 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 histidine decarboxylase knockout and H2-receptor knockout mice. Results: Lipopolysaccharide challenge after Propionibacterium acnes priming increased histidine decarboxylase 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)892-902
Number of pages11
Issue number3
Publication statusPublished - Sept 2004

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology


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