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From the Department of Pathology,*
University of Michigan Medical
School, Ann Arbor, Michigan; the Gladstone Institute of Cardiovascular
Disease,
University of California San
Francisco, San Francisco, California; and the Department of
Medicine,
University of Edinburgh, Edinburgh,
United Kingdom
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-
and TNF-
.
The in vivo immunoneutralization of IFN- or TNF-
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.
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