Inducible histamine protects mice from P. acnes-primed and LPS-induced hepatitis through H2-receptor stimulation.
OBJECTIVE
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.
Yokoyama
Minori
M
Department of Pharmacology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Yokoyama
Akira
A
Mori
Shuji
S
Takahashi
Hideo K
HK
Yoshino
Tadashi
T
Watanabe
Takeshi
T
Watanabe
Takehiko
T
Ohtsu
Hiroshi
H
Nishibori
Masahiro
M
D000818:Animals; D005260:Female; D016908:Gram-Positive Bacterial Infections / Q000150:complications* / Q000276:immunology; D006505:Hepatitis / Q000276:immunology; D006632:Histamine / Q000276:immunology*; D006640:Histidine Decarboxylase / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D020382:Interleukin-18 / Q000276:immunology; D008070:Lipopolysaccharides / Q000009:adverse effects*; D017093:Liver Failure / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D011425:Propionibacterium acnes; D011970:Receptors, Histamine H2 / Q000276:immunology*; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D020382:Interleukin-18; D008070:Lipopolysaccharides; D011970:Receptors, Histamine H2; D014409:Tumor Necrosis Factor-alpha; D006632:Histamine; D007371:Interferon-gamma; D006640:Histidine Decarboxylase