Alleviation of lipopolysaccharide-induced acute liver injury in Propionibacterium acnes-primed IFN-gamma-deficient mice by a concomitant reduction of TNF-alpha, IL-12, and IL-18 production.

The present study was designed to investigate the role of IFN-gamma in LPS-induced liver injury following priming with Propionibacterium acnes. At 1 week after priming BALB/c mice with P. acnes, a large number of macrophages (Mphi) and lymphocytes predominantly infiltrated the portal area, resulting in the intrahepatic formation of granulomas consisting of epithelioid and lymphoid cells. In comparison, in IFN-gamma gene-disrupted BALB/c mice (IFN-gamma knockout mice), the number of infiltrated Mphi was decreased, with a significant reduction in the number and size of granulomas. Subsequent elicitation with a low dose of LPS induced massive hepatic necrosis in wild-type BALB/c mice, with a marked increase in the serum levels of TNF-alpha, IL-12, and IL-18 and subsequently of alanine transferase. In contrast, IFN-gamma knockout mice developed scattered focal necrosis of the liver with significantly lower levels of serum alanine transferase as well as drastic decreases in TNF-alpha, IL-12, and IL-18 production. The administration of an anti-IFN-gamma neutralizing mAb at the eliciting phase significantly alleviated liver injury and reduced serum IL-12 and IL-18 levels. Thus, endogenously produced IFN-gamma is involved in the pathogenesis of this liver injury model by regulating Mphi infiltration and granuloma formation in the priming phase as well as cytokine production in the eliciting phase.