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Am J Physiol Gastrointest Liver Physiol (July 8, 2004). doi:10.1152/ajpgi.00184.2004
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Submitted on April 23, 2004
Accepted on July 1, 2004

IFN-{gamma}/STAT1 Acts as A Pro-inflammatory Signal in T Cell-mediated Hepatitis via Induction of Multiple Chemokines and Adhesion Molecules: A Critical Role of IRF-1

Barbara Jaruga1, Feng Hong1, Won-Ho Kim1, and Bin Gao1*

1 Section on Liver Biology, Laboratory of Physiologic Studies, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA

* To whom correspondence should be addressed. E-mail: bgao{at}mail.nih.gov.

We have previously shown that IFN-{gamma}/STAT1 plays an essential role in Concanavalin A (Con A)-induced T cell hepatitis via activation of apoptotic signaling pathways. Here we demonstrate that IFN-{gamma}/STAT1 also plays a crucial role in leukocyte infiltration into the liver in T cell hepatitis. After injection of Con A, leukocytes were significantly infiltrated into the liver, which was suppressed in IFN-{gamma} -/- and STAT1 -/- mice. Disruption of the IFN regulatory factor-1 (IRF-1) gene, a downstream target of IFN-{gamma}/STAT1, abolished Con A-induced liver injury and suppressed leukocyte infiltration into the liver. Additionally, Con A injection induced expression of a wide variety of chemokines and adhesion molecules in the liver. Among them, expression of ICAM-1, VCAM-1, Mig, CCL-20, ENA-78, ITAC, and IP-10 was markedly attenuated in IFN-{gamma} -/-, STAT1 -/- , and IRF-1 -/- mice. In primary mouse hepatocytes, Kupffer cells, and endothelial cells, in vitro treatment with IFN-{gamma} activated STAT1, STAT3, and IRF-1, and induced expression of VCAM-1, ICAM-1, Mig, ENA-78, I-TAC, and IP-10 mRNA. Induction of these chemokines and adhesion molecules was markedly diminished in STAT1-/- and IRF-1-/- hepatic cells compared to wild-type hepatic cells. These findings suggest that in addition to induction of apoptosis previously well documented, IFN-{gamma} also stimulated hepatocytes, sinusoidal endothelial cells, and Kupffer cells partly via an STAT1/IRF-1-dependent mechanism to produce multiple chemokines and adhesive molecules responsible for promoting infiltration of leukocytes and ultimately resulting in hepatitis.




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