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

Gastroenterology. 2004 Sep;127(3):892-902. doi: 10.1053/j.gastro.2004.06.020.


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 alpha in the liver, leading to the reduced plasma levels of cytokines including IL-18, TNF-alpha, IL-12, IFN-gamma, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Gram-Positive Bacterial Infections / complications*
  • Gram-Positive Bacterial Infections / immunology
  • Hepatitis / immunology
  • Histamine / immunology*
  • Histidine Decarboxylase / immunology
  • Interferon-gamma / immunology
  • Interleukin-18 / immunology
  • Lipopolysaccharides / adverse effects*
  • Liver Failure / immunology*
  • Liver Failure / microbiology
  • Male
  • Mice
  • Mice, Knockout
  • Models, Animal
  • Propionibacterium acnes*
  • Receptors, Histamine H2 / immunology*
  • Survival Analysis
  • Tumor Necrosis Factor-alpha / immunology


  • Interleukin-18
  • Lipopolysaccharides
  • Receptors, Histamine H2
  • Tumor Necrosis Factor-alpha
  • Histamine
  • Interferon-gamma
  • Histidine Decarboxylase