Regular Articles
Exaggerated Hepatic Injury Due to Acetaminophen Challenge in Mice Lacking C-C Chemokine Receptor 2

https://doi.org/10.1016/S0002-9440(10)64995-4Get rights and content

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 chemoattractant protein-1 (MCP-1. responses in the mouse. Accordingly, the present study 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 intraperitoneal injection of APAP (300 mg/kg). Liver and serum samples were removed from both groups of mice before and at 24 and 48 hours post APAP. Significantly elevated levels of MCP-1 were detected in liver samples from CCR2+/+ and CCR2−/− mice at 24 hours post-APAP. Although CCR2+/+ mice exhibited no liver injury at any time after receiving APAP, CCR2−/− mice exhibited marked evidence of necrotic and TUNEL-positive cells in the liver, particularly at 24 hours post-APAP. Enzyme-linked immunosorbent assay analysis of liver homogenates from both groups of mice at the 24 hours time point revealed that liver tissue from CCR2−/− mice contained significantly greater amounts of immunoreactive IFN-γ and TNF-α. The in vivo immunoneutralization of IFN-γ or TNF-α significantly attenuated APAP-induced liver injury in CCR2−/− mice and increased hepatic IL-13 levels. Taken together, these findings demonstrate that CCR2 expression in the liver provides a hepatoprotective effect through its regulation of cytokine generation during APAP challenge.

Cited by (0)

Supported by National Institutes of Health grants 1P50HL56402, 1P50HL60289, CA66180, HL35276, HL31963, and AI36302. K. J. S. was supported in part by the Medical Research Council of the United Kingdom and by Scottish Hospital Endowment Research Trust (1512).

View Abstract