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The role of histamine H₁ receptor and H₂ receptor in LPS-induced liver injury

Department of Internal Medicine, School of Medicine, Oita University, Oita, Japan; and
^* Laboratory for Immune Surveillance RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

¹Correspondence: Department of Internal Medicine, School of Medicine, Oita University, Hasama, Oita, 879-5593, Japan. E-mail: MASAKI{at}med.oita-u.ac.jp

To examine the role of histamine H₁ and H₂ receptors in the regulation of lipopolysaccharide (LPS)-induced liver injury, a combination of D-galactosamine and LPS (GalN/LPS) was administered to histamine H₁ receptor knockout (H₁-R KO) and H₂ receptor knockout (H₂-R KO) mice. The numbers of necrotic and apoptotic hepatocytes in the liver, as well as the levels of serum aspartate transaminase (AST) and alanine transaminase (ALT), were increased significantly by GalN/LPS treatment compared to the appropriate controls. Pretreatment with histamine ameliorated the GalN/LPS-induced necrotic and apoptotic changes in the hepatocytes and inhibited the elevation of serum AST and ALT levels. Histamine attenuated the GalN/LPS-induced increases in the levels of TNF-, but augmented those of IL-10 both in the liver and serum. Histamine inhibited the GalN/LPS-induced caspase-3 activity in the liver. Furthermore, these effects of histamine were completely or partially attenuated in H₂-R KO mice, but not in H₁-R KO mice. Peritoneal macrophages from H₂-R KO mice exhibited blunted changes in the effects of histamine on LPS-induced TNF- and IL-10 production in vitro compared to the wild-type (WT) controls. In summary, the present findings suggest that the histamine H₂-R-TNF- and -IL-10 pathways play protective roles in endotoxin-induced hepatic injury.—Masaki, T., Chiba, S., Tatsukawa, H., Noguchi, H., Kakuma, T., Endo, M., Seike, M., Watanabe, T., Yoshimatsu, H. The role of histamine H₁ receptor and H₂ receptor in LPS-induced liver injury.

Key Words: lipopolysaccharide • histamine receptor • tumor necrosis factor- • IL-10