title: Activation of innate immunity (NK/IFN-gamma) in rat allogeneic liver transplantation: contribution to liver injury and suppression of hepatocyte proliferation.
abstract: 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 p21(CDKN1A)) 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.
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Kezhen
authors.initials: K
authors.lastname: Shen
authors.forename: Shu-Sen
authors.initials: SS
authors.lastname: Zheng
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Zhaoli
authors.initials: Z
authors.lastname: Sun
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007108:Immune Tolerance; D007113:Immunity, Innate; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D008115:Liver Regeneration / Q000276:immunology; D016031:Liver Transplantation; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D015854:Up-Regulation
chemical_list: C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050856:Interferon Regulatory Factor-1; C494259:Irf1 protein, rat; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; D007371:Interferon-gamma