Constitutive androstane receptor (CAR) mediates pyrene‐induced inflammatory responses in mouse liver, with increased serum amyloid A proteins and Th17 cells

Background and Purpose The constitutive androstane receptor (CAR), a known xenobiotic sensor, plays an important role in drug metabolism by regulating numerous genes. The polycyclic aromatic hydrocarbon pyrene, an environmental pollutant, is a CAR activator and induces mouse hepatotoxicity via CAR. Here, we investigate the molecular mechanisms of the inflammatory response in pyrene‐caused mice liver injury. Experimental Approach Effects of pyrene on the liver were investigated in wild‐type and CAR knockout (KO) mice. Levels of pyrene and its urinary metabolite were analysed by high performance liquid chromatography (HPLC). Inflammatory responses were measured by qRT‐PCR, western blotting, and ELISA for cytokines. Key Results Serum amyloid A proteins (SAAs) were markedly increased in the liver and serum of pyrene‐exposed wild‐type mice. IL‐17‐producing helper T cells (Th17 cells) and IL‐17 levels were increased in the liver of pyrene‐exposed wild‐type mice. Hepatic mRNA levels of inflammatory cytokines including IL‐1β, IL‐6 and TNFα, and serum IL‐6 levels were significantly elevated in pyrene‐treated wild‐type mice. However, these changes were not observed in CAR KO mice. Conclusion and Implications CAR plays a crucial role in pyrene‐caused mice liver inflammatory response with increased SAAs and Th17 cells. Our results suggest that serum SAAs may be a convenient biomarker for early diagnosis of liver inflammatory response caused by polycyclic aromatic hydrocarbons, including pyrene. CAR and Th17 cells may be potential targets for novel therapeutic strategies for xenobiotic‐induced liver inflammation.