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1 Liver Center and Department of Medicine, University of California San Francisco, San Francisco, CA, USA
2 Center for Liver Diseases and Transplantation, Cedars-Sinai Medical Center, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: jmaher{at}medsfgh.ucsf.edu.
Alpha-naphthylisothiocyanate (ANIT) is a hepatotoxin that causes severe neutrophilic inflammation around portal tracts and bile ducts. The chemotactic signals that provoke this inflammatory response are unknown. In this study, we addressed the possibility that ANIT up-regulates CXC chemokines in the liver; we also investigated whether chemokines mediate hepatic inflammation and tissue injury in ANIT-treated livers. Mice treated with a single dose of ANIT (50 mg/kg) exhibited rapid hepatic induction of the CXC chemokine macrophage inflammatory protein-2 (MIP-2). MIP-2 derived primarily from hepatocytes, with no apparent contribution by biliary cells. In ANIT-treated mice, the induction of MIP-2 coincided with an influx of neutrophils to portal zones; this hepatic neutrophil recruitment was suppressed by 50% in mice that lack the receptor for MIP-2 (CXCR2-/-). Interestingly, despite their markedly reduced degree of hepatic inflammation, CXCR2-/- mice displayed just as much hepatocellular injury and cholestasis after ANIT treatment as wild-type mice. Moreover, long-term exposure of CXCR2-/- mice to ANIT induced liver fibrosis that was indistinguishable from that in wild-type mice. In summary, our data show that CXC chemokines are responsible for some of the hepatic inflammation that occurs in response to ANIT, but that these compounds are not essential to the pathogenesis of either acute or chronic ANIT hepatotoxicity.
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