Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C chemokine receptor 2

Monocyte chemoattractant protein-1 is one of the major C-C chemokines that has been implicated in liver injury. The C-C chemokine receptor, CCR2, has been identified as the primary receptor that mediates monocyte chemoattract ant protein-1 (MCP-1) responses in the mouse. Accordingly, the present stud y addressed the role of CCR2 in mice acutely challenged with acetaminophen (APAP). Mice genetically deficient in CCR2 (CCR2(-/-)) and their wild-type counterparts (CCR2(+/+)) were fasted for 10 hours before receiving an intra peritoneal injection of APAP (300 mg/kg), Liver and serum samples were remo ved from both groups of mice before and at 24 and 48 hours post APAP, Signi ficantly elevated levels of MCP-1 were detected in liver samples from CCR2( +/+) and CCR2(-/-) mice at 24 hours post-APAP. Although CCR2(+/+) mice exhi bited no liver injury at any time after receiving APAP, CCR2(-/-) mice exhi bited marked evidence of necrotic and TUNEL-positive cells in the liver, pa rticularly at 24 hours post-APAP, Enzyme-linked immunosorbent assay analysi s of liver homogenates from both groups of mice at the 24 hours time point revealed that liver tissue from CCR2(-/-) mice contained significantly grea ter amounts of immunoreactive IFN-gamma and TNF-alpha. The in vivo immunone utralization of IFN-gamma or TNF-alpha significantly attenuated APAP-induce d liver injury in CCR2(-/-) mice and increased hepatic IL-13 levels. Taken together, these findings demonstrate that CCR2 expression in the liver prov ides a hepatoprotective effect through its regulation of cytokine generatio n during APAP challenge.