title: Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C chemokine receptor 2.
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-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.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA. hogaboam@path.med.umich.edu
authors.forename: C M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: C L
authors.initials: CL
authors.lastname: Bone-Larson
authors.forename: M L
authors.initials: ML
authors.lastname: Steinhauser
authors.forename: A
authors.initials: A
authors.lastname: Matsukawa
authors.forename: J
authors.initials: J
authors.lastname: Gosling
authors.forename: L
authors.initials: L
authors.lastname: Boring
authors.forename: I F
authors.initials: IF
authors.lastname: Charo
authors.forename: K J
authors.initials: KJ
authors.lastname: Simpson
authors.forename: N W
authors.initials: NW
authors.lastname: Lukacs
authors.forename: S L
authors.initials: SL
authors.lastname: Kunkel
mesh_terms: D000082:Acetaminophen / Q000506:poisoning*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis; D056486:Chemical and Drug Induced Liver Injury; D018932:Chemokine CCL2 / Q000378:metabolism; D007106:Immune Sera / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008107:Liver Diseases / Q000473:pathology; D051379:Mice; D009336:Necrosis; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D007106:Immune Sera; D018793:Interleukin-13; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D000082:Acetaminophen; D007371:Interferon-gamma