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 (P. acnes) and LPS. The expression of HO-1 mRNA and of protein in the liver was increased after repeated administrations of 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, administrations of 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 of protein in dendritic cells (DCs) was increased after administration of cobalt protoporphyrin IX. HO-1 decreased the mature markers MHCII 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 Th1 polarization of liver infiltrating CD4⁺ T cells and reduced the production of serum alanine aminotransferase and pro-inflammatory cytokines such as IFN-γ and TNF-α. Taken together, our data suggest that HO-1 alleviates P. acnes/LPS induced fulminant hepatic failure, probably by inhibiting DC-induced adaptive responses.