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

Am J Pathol. 2000 Apr;156(4):1245-52. doi: 10.1016/S0002-9440(10)64995-4.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetaminophen / poisoning*
  • Animals
  • Antibodies / immunology
  • Apoptosis
  • Chemical and Drug Induced Liver Injury*
  • Chemokine CCL2 / metabolism
  • Immune Sera / immunology
  • Interferon-gamma / metabolism
  • Interleukin-13 / immunology
  • Interleukin-13 / metabolism
  • Liver / drug effects*
  • Liver / metabolism*
  • Liver / pathology
  • Liver / physiopathology
  • Liver Diseases / pathology
  • Mice
  • Necrosis
  • Receptors, CCR2
  • Receptors, Chemokine / deficiency*
  • Receptors, Chemokine / metabolism
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism


  • Antibodies
  • Ccr2 protein, mouse
  • Chemokine CCL2
  • Immune Sera
  • Interleukin-13
  • Receptors, CCR2
  • Receptors, Chemokine
  • Tumor Necrosis Factor-alpha
  • Acetaminophen
  • Interferon-gamma