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

Cory M. Hogaboam, Cynthia L. Bone-Larson, Matthew L. Steinhauser, Akihiro Matsukawa, Jennifa Gosling, Landin Boring, Israel F. Charo, Kenneth J. Simpson, Nicholas W. Lukacs, Steven L. Kunkel

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Abstract

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.

Original languageEnglish
Pages (from-to)1245-1252
Number of pages8
JournalAmerican Journal of Pathology
Volume156
Issue number4
DOIs
Publication statusPublished - Jan 1 2000

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

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. (2000). Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C chemokine receptor 2. American Journal of Pathology, 156(4), 1245-1252. https://doi.org/10.1016/S0002-9440(10)64995-4