Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Hogaboam, C.M. et al.

Hogaboam, Bone-Larson, Steinhauser, Matsukawa, Gosling, Boring, Charo, Simpson, Lukacs, Kunkel,

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 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-gamma and TNF-alpha. The in vivo immunoneutralization of IFN-gamma or TNF-alpha 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.[1]

References

Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C chemokine receptor 2. Hogaboam, C.M., Bone-Larson, C.L., Steinhauser, M.L., Matsukawa, A., Gosling, J., Boring, L., Charo, I.F., Simpson, K.J., Lukacs, N.W., Kunkel, S.L. Am. J. Pathol. (2000) [Pubmed]

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