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Am J Physiol Gastrointest Liver Physiol 294: G1070-G1077, 2008. First published February 21, 2008; doi:10.1152/ajpgi.00554.2007
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LIVER AND BILIARY TRACT

Activation of innate immunity (NK/IFN-{gamma}) in rat allogeneic liver transplantation: contribution to liver injury and suppression of hepatocyte proliferation

Kezhen Shen,1,2 Shu-Sen Zheng,1 Ogyi Park,2 Hua Wang,2,4 Zhaoli Sun,3 and Bin Gao2

1Department of Hepatobiliary Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; 2Section on Liver Biology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; 3Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; 4Department of Oncology, The Affiliated Provincial Hospital of Anhui Medical University, Anhui, China

Submitted 27 November 2007 ; accepted in final form 20 February 2008

Liver transplantation is presently the only curative treatment for patients with end-stage liver disease. However, the mechanisms underlying liver injury and hepatocyte proliferation posttransplantation remain obscure. In this investigation, liver injury and hepatocyte proliferation in syngeneic and allogeneic animal models were compared. Male Lewis and Dark Agouti (DA) rats were subjected to orthotopic liver transplantation (OLT). Rat OLT was performed in syngeneic (Lewis-Lewis) and allogeneic (Lewis-DA or DA-Lewis) animal models. Allogeneic liver grafts exhibited greater injury and cellular apoptosis than syngeneic grafts but less hepatocyte proliferation after OLT. Expression of IFN-{gamma} mRNA and activation of the downstream signal transducer and activator of transcription 1 (STAT1) and genes (interferon regulatory factor-1 and cyclin-dependent kinase inhibitor p21CDKN1A) were also greater in the allogeneic grafts compared with the syngeneic grafts. In contrast, STAT3 activation was lower in the allogeneic grafts. Furthermore, in the allogeneic grafts, depletion of natural killer (NK) cells decreased IFN-{gamma}/STAT1 activation but enhanced hepatocyte proliferation. These findings suggest that, compared with syngeneic transplantation, innate immunity (NK/IFN-{gamma}) is activated after allogeneic transplantation, which likely contributes to liver injury and inhibits hepatocyte proliferation.

liver regeneration; NK cells; STAT1; IRF-1; p21


Address for reprint requests and other correspondence: B. Gao, Sect. on Liver Biology, NIAAA/NIH, 5625 Fishers Ln., Rm. 2S-33, Bethesda, MD 20892 (e-mail: bgao{at}mail.nih.gov)






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