title: Heme oxygenase-1 alleviates mouse hepatic failure through suppression of adaptive immune responses.
abstract: Heme oxygenase-1 (HO-1) has protective effects on liver damage induced by noxious stimuli. The mechanism of action of HO-1 is not well understood. In the present study, we investigate the effect of HO-1 in a model of fulminant hepatic failure induced by Propionibacterium acnes and lipopolysaccharide (LPS). The expression of HO-1 mRNA and protein in the liver was increased after repeated administration of the HO-1 inducer cobalt protoporphyrin IX. We found that HO-1 protected mice from acute liver damage induced by P. acnes/LPS and prolonged survival. On the contrary, administration of the HO-1 inhibitor zinc protoporphyrin IX increased liver damage induced by P. acnes/LPS. Subsequently, to investigate the underlying mechanisms of HO-1 in the acute liver injury model, we primed mice with P. acnes only. We found that the expression of HO-1 mRNA and protein in dendritic cells (DCs) was increased after the administration of cobalt protoporphyrin IX. HO-1 decreased the mature markers major histocompatibility complex II and CD80 on liver DCs. The expression of CCR7, CCL2, and CCL22 mRNA, which are expressed by mature DCs, was also reduced. These liver DCs could not efficiently stimulate CD4+ T cell activation and proliferation. Consequently, HO-1 inhibited the activation, proliferation, and T helper 1 polarization of liver-infiltrating CD4+ T cells and reduced the production of serum alanine aminotransferase and proinflammatory cytokines such as interferon-γ and tumor necrosis factor-α. Taken together, our data suggest that HO-1 alleviates P. acnes/LPS-induced fulminant hepatic failure, probably by inhibiting DC-induced adaptive responses.
authors.affiliation: Shanghai Institute of Immunology, Shanghai Institutes for Biological Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Gu
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.forename: Min
authors.initials: M
authors.lastname: Jin
authors.forename: Yichuan
authors.initials: Y
authors.lastname: Xiao
authors.forename: Jingwei
authors.initials: J
authors.lastname: Xu
authors.forename: Chaoming
authors.initials: C
authors.lastname: Mao
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000502:physiology*; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000473:pathology; D017114:Liver Failure, Acute / Q000188:drug therapy* / Q000276:immunology*; D008111:Liver Function Tests; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D011425:Propionibacterium acnes / Q000737:chemistry; D011524:Protoporphyrins / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D013534:Survival
chemical_list: D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1; D001219:Aspartate Aminotransferases