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Regular Article| Volume 88, ISSUE 2, P142-149, February 2000

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c-Jun Does Not Mediate Hepatocyte Apoptosis Following NFκB Inhibition and Partial Hepatectomy

DOI:https://doi.org/10.1006/jsre.1999.5784
c-Jun Does Not Mediate Hepatocyte Apoptosis Following NFκB Inhibition and Partial Hepatectomy
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      Abstract

      Inhibition of the transcription factor nuclear factor kappa B (NFκB) induces marked hepatocyte apoptosis and liver dysfunction after partial hepatectomy (PH) in rats. Hepatocyte apoptosis may be due to direct inhibition of NFκB-induced hepatocyte survival genes or due to indirect increased signaling through the stress-activated protein kinase pathway (SAPK), resulting in increased c-Jun. c-Jun, an AP-1 transcription factor, induces apoptosis in fibroblasts. Our aim was to determine if hepatocyte apoptosis following inhibition of NFκB and partial hepatectomy in rats is due to increased c-Jun. Adult male Sprague–Dawley rats (200 g) were injected intraportally with 6 × 109 PFU adenoviral vector containing luciferase (Ad5Luc) or superrepressor IκB (Ad5IκB) transgene that inhibits NFκB translocation into the nucleus. Two-thirds PH was performed 24 h after vector administration, and the remnant liver was harvested 30 min or 24 h after PH. Northern and Western blots were performed to examine the presence of IκB and c-Jun. A GST c-Jun kinase assay was used to examine Jun-N-terminal kinase (JNK) activity. AP-1 DNA binding activity was assessed by electrophoretic mobility shift assay. TUNEL assay was performed to assess apoptosis. All rats receiving adenoviral vectors expressed the luciferase or superrepressor IκB transgenes. c-Jun mRNA, protein levels, and DNA binding activity were not increased in rats treated with Ad5IκB at 30 min after PH compared to rats injected with Ad5Luc. Jun kinase activity increased following partial hepatectomy, but activity was similar in Ad5Luc- and Ad5IκB-treated animals. AP-1 DNA binding activity was not altered substantially in rats treated with Ad5IκB. The percentage of apoptotic hepatocytes was similar between Ad5Luc- and Ad5IκB-injected animals at 0 h, but livers from Ad5IκB-treated rats had increased apoptosis at 24 h compared to Ad5Luc rats (24% vs. 4%) after PH. Hepatocyte apoptosis after NFκB inhibition and PH is not mediated by increased JNK activity or c-Jun.

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      References

      REFERENCES

        • Andus T.
        • Bauer J.
        • Gerok W.
        Effects of cytokines on the liver.
        Hepatology. 1991; 13: 364
        • Fausto N.
        • Laird D.
        • Webber E.
        Role of growth factors and cytokines in hepatic regeneration.
        FASEB J. 1995; 9: 1527
        • Michalopoulos G.
        Liver regeneration: Molecular mechanisms of growth control.
        FASEB J. 1990; 4: 176
        • Cressman D.
        • Greenbaum L.
        • DeAngelis R.
        • Ciliberto G.
        • Furth E.
        • Poli V.
        • Taub R.
        Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice.
        Science. 1996; 274: 1379
        • Taub R.
        Transcriptional control of liver regeneration.
        FASEB J. 1996; 10: 413
        • Akerman P.
        • Cote P.
        • Yang S.
        • McClain C.
        • Nelson S.
        • Bagby G.
        • Diehl A.
        Antibodies to tumor necrosis factor-alpha inhibit liver regeneration after partial hepatectomy.
        Am. J. Physiol. 1992; 263: G579
        • Cressman D.
        • Diamond R.
        • Taub R.
        Rapid activation of the Stat3 transcription complex in liver regeneration.
        Hepatology. 1995; 21: 1443
        • Yamada Y.
        • Webber E.
        • Kirillova I.
        • Peschon J.
        • Fausto N.
        Analysis of liver regeneration in mice lacking type 1 or 2 tumor necrosis factor receptor: Requirement for type 1 but not type 2 receptor.
        Hepatology. 1998; 28: 959
        • Iimuro Y.
        • Nishiura T.
        • Hellerbrand C.
        • Behrns K.
        • Schoonhoven R.
        • Grisham J.
        • Brenner D.
        NFκB prevents apoptosis and liver dysfunction during liver regeneration.
        J. Clin. Invest. 1998; 101: 802
        • Webber E.
        • Godowski P.
        • Fausto N.
        In vivo response of hepatocytes to growth factor requires an initial priming stimulus.
        Hepatology. 1994; 14: 489
        • Hsu H.
        • Xiong J.
        • Goeddel D.
        The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation.
        Cell. 1995; 81: 495
        • Hsu H.
        • Shu H.
        • Pan M.
        • Goedell D.
        TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways.
        Cell. 1996; 84: 299
        • Wang C.-Y.
        • Mayo M.
        • Korneluk R.
        • Goeddel D.
        • Baldwin Jr., A.S.
        NF-kB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation.
        Science. 1998; 281: 1680
        • Wu M.
        • Ao Z.
        • Prasad K.
        • Wu R.
        • Schlossman S.
        IEX-1L, an apoptosis inhibitor involved in NF-kB-mediated survival.
        Science. 1998; 281: 998
        • Kim Y.
        • Talanian R.
        • Billiar T.
        Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms.
        J. Biol. Chem. 1997; 272: 31138
        • Song H.
        • Regnier C.
        • Kirshning C.
        • Goeddel D.
        • Rothe M.
        Tumor necrosis factor (TNF)-mediated kinase cascades: Bifurcation of nuclear factor-kB and c-Jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor-2.
        Proc. Natl. Acad. Sci. USA. 1997; 94: 9792
        • Westwick J.
        • Weitzel C.
        • Leffert H.
        • Brenner D.
        Activation of Jun kinase is an early event in hepatic regeneration.
        J. Clin. Invest. 1995; 1995: 803
        • Hilberg F.
        • Aguzzi A.
        • Howells N.
        • Wagner E.
        c-Jun is essential for normal mouse development and hepatogenesis.
        Nature. 1993; 365: 179
        • Kyriakis J.
        • Banerjee P.
        • Nikolakaki E.
        • Dai T.
        • Rubie E.
        • Ahmad M.
        • Avruch J.
        • Woodgett J.R.
        The stress-activated protein kinase subfamily of c-Jun kinases.
        Nature. 1994; 369: 156
        • Guo Y.-L.
        • Baysal K.
        • Kang B.
        • Yang L.-J.
        • Williamson J.
        Correlation between sustained c-Jun N-terminal protein kinase activation and apoptosis induced by tumor necrosis factor-alpha in rat mesangial cells.
        J. Biol. Chem. 1998; 273: 4027
        • Bossy-Wetzel E.
        • Bakiri L.
        • Yaniv M.
        Induction of apoptosis by the transcription factor c-Jun.
        EMBO J. 1997; 16: 1695
        • Chen Y.
        • Wang X.
        • Templeton D.
        • Davis R.
        • Tan T.
        The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma irradiation.
        J. Biol. Chem. 1996; 1996: 31929
        • Sawai H.
        • Okazaki T.
        • Yamamoto H.
        • Okano H.
        • Takeda Y.
        • Tashima M.
        Requirement of AP-1 for ceramide-induced apoptosis in human leukemia HL-60 cells.
        J. Biol. Chem. 1995; 270: 27326
        • Verheij M.
        • Bose R.
        • Lin X.
        • Yao B.
        • Jarvis W.
        • Grant S.
        • Birrer M.
        Requirement for ceramide-initiated SAPK/JNK signaling in stress-induced apoptosis.
        Nature. 1996; 380: 75
        • Xia Z.
        • Dickens M.
        • Raingeaud J.
        • Davis R.
        • Greenberg M.
        Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis.
        Science. 1995; 270: 1326
        • Yang D.
        • Kuan C.
        • Whitmarsh A.
        • Rincon M.
        • Zheng M.
        • Davis R.
        • Rakie P.
        • Flavell R.
        Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the JNK3 gene.
        Nature. 1997; 389: 865
        • Chauhan D.
        • Pandy P.
        • Ogata A.
        • Teoh G.
        • Treon S.
        • Urashima M.
        • Kharbanda S.
        • Anderson K.
        Dexamethasone induces apoptosis of multiple myeloma cells in a JNK/SAP kinase independent mechanism.
        Oncogene. 1997; 15: 837
        • Ishizuka T.
        • Sakata N.
        • Johnson G.
        • Gelfand E.
        • Terada N.
        Rapamycin potentiates dexamethasone-induced apoptosis and inhibits JNK activity in lymphoblastoid cells.
        Biochem. Biophys. Res. Commun. 1997; 230: 386
        • Lenczowski J.
        • Dominguez L.
        • Eder A.
        • King L.
        • Zacharchuk C.
        • Ashwell J.
        Lack of a role for jun kinase and AP-1 in Fas-induced apoptosis.
        Mol. Cell. Biol. 1997; 17: 170
        • Liu Z.
        • Hsu H.
        • Goeddel D.
        • Karin M.
        Dissection of TNF receptor I effector functions: JNK activation is not linked to apoptosis while NF-kB activation prevents cell death.
        Cell. 1996; 87: 565
        • Natoli G.
        • Costanzo A.
        • Ianni A.
        • Templeton D.
        • Woodgett J.
        • Balsano C.
        • Levrero M.
        Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway.
        Science. 1997; 275: 200
        • Roffler-Tarlov S.
        • Jeremy J.
        • Brown G.
        • Tarlov E.
        • Stolarov J.
        • Chapman D.
        • Alexiou M.
        • Papaioannou V.
        Programmed cell death in the absence of c-Fos and c-Jun.
        Development. 1996; 122: 1
        • Smith A.
        • Ramos-Morales F.
        • Ashworth A.
        • Collins M.
        A role for JNK/SAPK in proliferation, but not apoptosis, of IL-3-dependent cells.
        Curr. Biol. 1997; 7: 893
        • Xing Z.
        • Ohkawara Y.
        • Jordana M.
        • Graham F.
        • Gauldie J.
        Transfer of granulocyte-macrophage colon-stimulating factor gene to rat lung induces eosinophilia.
        J. Clin. Invest. 1996; 97: 1102
        • Maizel J.
        • White D.
        • Scharff M.
        The polypeptides of adenovirus. II. Soluble proteins, top components and the structure of the virion.
        Virology. 1968; 36: 126
        • Higgins G.
        • Anderson R.
        Experimental pathology of the liver: Restoration of the liver of the white rat following partial surgical removal.
        Arch. Pathol. 1931; 12: 186
        • Sambrook J.
        • Fritsch E.
        • Maniatis T.
        Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press, Plainview1989
        • Dignam J.
        • Lebovitz R.
        • Roeder R.
        Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei.
        Nucleic Acids Res. 1983; 11: 1475
        • Rippe R.
        • Almounajed G.
        • Brenner D.
        Sp1 binding activity increases in activated Ito cells.
        Hepatology. 1995; 22: 241
        • Alcorn J.
        • Feitelberg S.
        • Brenner D.
        Transient induction of c-Jun during hepatic regeneration.
        Hepatology. 1990; 11: 909
        • Strain A.
        • Frazer A.
        • Hill D.
        • Milner R.
        Transforming growth factor β inhibits DNA synthesis in hepatocytes isolated from normal and regenerating rat livers.
        Biochem. Biophys. Res. Commun. 1987; 145: 436
        • Nakamura T.
        • Tomita Y.
        • Hirai R.
        • Yamaoka K.
        • Kaji K.
        • Ichihara A.
        Inhibitory effect of transforming growth factor-B on DNA synthesis of adult rat hepatocytes in primary culture.
        Biochem. Biophys. Res. Commun. 1985; 133: 1042
        • Russell W.
        • Coffey R.
        • Ouellette A.
        • Moses H.
        Type B transforming growth factor reversibly inhibits the early proliferative response to partial hepatectomy in the rat.
        Proc. Natl. Acad. Sci. USA. 1988; 85: 5126
        • Fitzgerald M.
        • Webber E.
        • Donovan J.
        • Fausto N.
        Rapid DNA binding by nuclear factor kB in hepatocytes at the start of liver regeneration.
        Cell Growth Differ. 1995; 6: 417
        • Beg A.
        • Sha W.
        • Bronson R.
        • Ghosh S.
        • Baltimore D.
        Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kB.
        Nature. 1995; 376: 167
        • Bellas R.
        • FitzGerald M.
        • Fausto N.
        • Sonenshein G.
        Inhibition of NF-kB activity induces apoptosis in murine hepatocytes.
        Am. J. Pathol. 1997; 151: 891
        • Wang C.-Y.
        • Mayo M.
        • Baldwin A.
        TNF- and cancer therapy-induced apoptosis: Potentiation by inhibiting NFkB.
        Science. 1996; 274: 784
        • Chang H.
        • Nishitoh H.
        • Yang X.
        • Ichijo H.
        • Baltimore D.
        Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx.
        Science. 1998; 281: 1860
        • Lacronique V.
        • Mignon A.
        • Fabre M.
        • Viollet B.
        • Rouquet N.
        • Molina T.
        • Porteu A.
        • Henrion A.
        • Bouscary D.
        • Varlet P.
        • Joulin V.
        • Kahn A.
        Bcl-2 protects from lethal hepatic apoptosis induced by an anti-Fas antibody in mice.
        Nature Med. 1996; 2: 80

      Article info

      Footnotes

      ☆Supported by Grant DK34987 from the Center for Gastrointestinal Biology and Disease, University of North Carolina. Portions of this work were published in abstract form (Hepatology, 28:328A, 1998) and presented at the 49th annual meeting of the American Association for the Study of Liver Disease, Chicago, Illinois, November 8, 1998.

      Identification

      DOI: https://doi.org/10.1006/jsre.1999.5784

      Copyright

      © 2000 Academic Press. Published by Elsevier Inc. All rights reserved.

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