Molecular Dissection of gp130-dependent Pathways in Hepatocytes during Liver Regeneration

Abstract

Interleukin-6 (IL-6) via its signal transducer gp130 is an important mediator of liver regeneration involved in protecting from lipopolysaccharide (LPS)-induced liver injury after partial hepatectomy (PH). Here we generated mice either defective (Δ) in hepatocyte-specific gp130-dependent Ras or STAT activation to define their role during liver regeneration. Deletion of gp130-dependent signaling had major impact on acute phase gene (APG) regulation after PH. APG expression was blocked in gp130-ΔSTAT animals, whereas gp130-ΔRas mice showed an enhanced APG response and stronger SOCS3 regulation correlating with delayed hepatocyte proliferation. To define the role of SOCS3 during hepatocyte proliferation, primary hepatocytes were co-stimulated with IL-6 and hepatocyte growth factor. Higher SOCS3 expression in gp130-ΔRas hepatocytes correlated with delayed hepatocyte proliferation. Next, we tested the impact of LPS, mimicking bacterial infection, on liver regeneration. LPS and PH induced SOCS3 and APG in all animal strains and delayed cell cycle progression. Additionally, IL-6/gp130-dependent STAT3 activation in hepatocytes was essential in mediating protection and thus required for maximal proliferation. Unexpectedly, oncostatin M was most strongly induced in gp130-ΔSTAT animals after PH/LPS-induced stress and was associated with hepatocyte proliferation in this strain. In summary, gp130-dependent STAT3 activation and concomitant SOCS3 during liver regeneration is involved in timing of DNA synthesis and protects hepatocyte proliferation during stress conditions. Interleukin-6 (IL-6) via its signal transducer gp130 is an important mediator of liver regeneration involved in protecting from lipopolysaccharide (LPS)-induced liver injury after partial hepatectomy (PH). Here we generated mice either defective (Δ) in hepatocyte-specific gp130-dependent Ras or STAT activation to define their role during liver regeneration. Deletion of gp130-dependent signaling had major impact on acute phase gene (APG) regulation after PH. APG expression was blocked in gp130-ΔSTAT animals, whereas gp130-ΔRas mice showed an enhanced APG response and stronger SOCS3 regulation correlating with delayed hepatocyte proliferation. To define the role of SOCS3 during hepatocyte proliferation, primary hepatocytes were co-stimulated with IL-6 and hepatocyte growth factor. Higher SOCS3 expression in gp130-ΔRas hepatocytes correlated with delayed hepatocyte proliferation. Next, we tested the impact of LPS, mimicking bacterial infection, on liver regeneration. LPS and PH induced SOCS3 and APG in all animal strains and delayed cell cycle progression. Additionally, IL-6/gp130-dependent STAT3 activation in hepatocytes was essential in mediating protection and thus required for maximal proliferation. Unexpectedly, oncostatin M was most strongly induced in gp130-ΔSTAT animals after PH/LPS-induced stress and was associated with hepatocyte proliferation in this strain. In summary, gp130-dependent STAT3 activation and concomitant SOCS3 during liver regeneration is involved in timing of DNA synthesis and protects hepatocyte proliferation during stress conditions. The liver has the unique capacity to compensate tissue loss after injury through hyperplasia of remaining hepatocytes while keeping its organ-specific functions (1Fausto N. Laird A.D. Webber E.M. FASEB J. 1995; 9: 1527-1536Crossref PubMed Scopus (566) Google Scholar, 2Michalopoulos G.K. DeFrances M.C. Science. 1997; 276: 60-66Crossref PubMed Scopus (2853) Google Scholar). Liver mass is controlled in an intriguingly exact way, which becomes essential in situations where transplanted livers that are too small for matching the body weight of the recipient have to grow until they reach their optimal size, whereas transplants that are too big in size shrink to their optimal volume (3Deshpande R.R. Bowles M.J. Vilca-Melendez H. Srinivasan P. Girlanda R. Dhawan A. Mieli-Vergani G. Muiesan P. Heaton N.D. Rela M. Annals Surg. 2002; 236: 248-253Crossref PubMed Scopus (95) Google Scholar, 4Kadry Z. Selzner N. Selzner M. Clavien P.A. Liver Transpl. 2004; 10: 1078Crossref PubMed Scopus (3) Google Scholar, 5Kim J.S. Groteluschen R. Mueller T. Ganschow R. Bicak T. Wilms C. Mueller L. Helmke K. Burdelski M. Rogiers X. Broering D.C. Transplantation. 2005; 79: 1206-1209Crossref PubMed Scopus (41) Google Scholar). Partial (two-thirds) hepatectomy (PH) 2The abbreviations used are:PHpartial hepatectomyILinterleukinLPSlipopolysaccharideAPGacute phase geneHGFhepatocyte growth factorSTATsignal transducers and activators of transcriptionErkextracellular signal-regulated kinaseOSMoncostatin MBrdUrd5-bromo-2′-deoxyuridineGAPDHglyceraldehyde-3-phosphate dehydrogenasewtwild typeSAAserum amyloid ACdkcyclin-dependent kinaseRTreverse transcription.2The abbreviations used are:PHpartial hepatectomyILinterleukinLPSlipopolysaccharideAPGacute phase geneHGFhepatocyte growth factorSTATsignal transducers and activators of transcriptionErkextracellular signal-regulated kinaseOSMoncostatin MBrdUrd5-bromo-2′-deoxyuridineGAPDHglyceraldehyde-3-phosphate dehydrogenasewtwild typeSAAserum amyloid ACdkcyclin-dependent kinaseRTreverse transcription. in rodents is a well established model for studying liver regeneration and cell cycle regulation in vivo. In this model it has been a major challenge to evaluate the extra- and intracellular events that orchestrate this highly complex process. To undergo distinct stages including priming, cell cycle progression, and cessation of regeneration, fully differentiated hepatocytes are forced to leave their quiescent state (6Darnell Jr., J.E. Science. 1997; 277: 1630-1635Crossref PubMed Scopus (3330) Google Scholar, 7Ihle J.N. Cell. 1996; 84: 331-334Abstract Full Text Full Text PDF PubMed Scopus (1258) Google Scholar). partial hepatectomy interleukin lipopolysaccharide acute phase gene hepatocyte growth factor signal transducers and activators of transcription extracellular signal-regulated kinase oncostatin M 5-bromo-2′-deoxyuridine glyceraldehyde-3-phosphate dehydrogenase wild type serum amyloid A cyclin-dependent kinase reverse transcription. partial hepatectomy interleukin lipopolysaccharide acute phase gene hepatocyte growth factor signal transducers and activators of transcription extracellular signal-regulated kinase oncostatin M 5-bromo-2′-deoxyuridine glyceraldehyde-3-phosphate dehydrogenase wild type serum amyloid A cyclin-dependent kinase reverse transcription. Growth factors and cytokines have been shown to play important roles in regulating this process. In the priming phase of hepatocytes, roles for cytokines like tumor necrosis factor α and IL-6 have been reported (8Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Crossref PubMed Scopus (1291) Google Scholar, 9Leu J.I. Crissey M.A. Leu J.P. Ciliberto G. Taub R. Mol. Cell. Biol. 2001; 21: 414-424Crossref PubMed Scopus (116) Google Scholar, 10Li W. Liang X. Kellendonk C. Poli V. Taub R. J. Biol. Chem. 2002; 277: 28411-28417Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 11Streetz K.L. Luedde T. Manns M.P. Trautwein C. Gut. 2000; 47: 309-312Crossref PubMed Scopus (190) Google Scholar, 12Trautwein C. Rakemann T. Niehof M. Rose-John S. Manns M.P. Gastroenterology. 1996; 110: 1854-1862Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). First, it was suggested that both are directly involved in mediating cell cycle progression. However, in recent years, especially for IL-6, it has been demonstrated that this cytokine does not directly control hepatocyte proliferation after PH but activates signaling pathways that are protective for the progression of regeneration (13Wuestefeld T. Klein C. Streetz K.L. Betz U. Lauber J. Buer J. Manns M.P. Muller W. Trautwein C. J. Biol. Chem. 2003; 278: 11281-11288Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). For signal transduction IL-6 first binds to the IL-6 receptor gp80. As a result these proteins build a complex with two gp130 signal transducers, which in turn results in the intracellular dimerization of these glycoproteins (14Taga T. Kishimoto T. Annu. Rev. Immunol. 1997; 15: 797-819Crossref PubMed Scopus (1280) Google Scholar). This event triggers activation of Janus kinases in the cell, which phosphorylated distinct intracellular tyrosines of the gp130 receptor. They serve as docking sites and activate the downstream pathways. In the gp130 molecule six tyrosine residues have been defined (15Hirano T. Int. Rev. Immunol. 1998; 16: 249-284Crossref PubMed Scopus (651) Google Scholar). Phosphorylation of the four distal tyrosines is involved in mediating nuclear translocation of STAT3 and STAT1, whereas phosphorylation of the second most membrane-proximal tyrosine is linked to the Ras/Erk pathway as well as to negative regulation of gp130 signaling (16Fukada T. Hibi M. Yamanaka Y. Takahashi-Tezuka M. Fujitani Y. Yamaguchi T. Nakajima K. Hirano T. Immunity. 1996; 5: 449-460Abstract Full Text Full Text PDF PubMed Scopus (581) Google Scholar, 17Gerhartz C. Heesel B. Sasse J. Hemmann U. Landgraf C. Schneider-Mergener J. Horn F. Heinrich P.C. Graeve L. J. Biol. Chem. 1996; 271: 12991-12998Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). In an earlier study we used conditional gp130 knock-out (LoxP/Cre system) mice to better characterize the role of IL-6-dependent signaling during liver regeneration. In these mice gp130 was deleted using a transgene for Cre, where its expression is controlled via the Mx promoter (MxCre gp130LoxP/LoxP) (13Wuestefeld T. Klein C. Streetz K.L. Betz U. Lauber J. Buer J. Manns M.P. Muller W. Trautwein C. J. Biol. Chem. 2003; 278: 11281-11288Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). Therefore, this approach had the advantage of deleting gp130 on demand but was active in all cells that are sensitive to interferon. The MxCre gp130LoxP/LoxP mice had a severe phenotype after PH, when they were co-stimulated with LPS. A high percentage, in contrast to controls, of the animals died and showed impaired hepatocyte proliferation. These results stressed two important questions: whether this phenotype is related to deletion of gp130 in hepatocytes and which of the two pathways, Ras/Erk and/or STAT, is involved in mediating protection during liver regeneration. Therefore, in the present study we used hepatocyte-specific gp130 knock-out (AlfpCre gp130LoxP/LoxP) mice and combined these animals with gp130 knock-in mice, deficient for either hepatocyte-specific gp130-dependent Ras/Erk (AlfpCre gp130Y757F/LoxP) or STAT (AlfpCre gp130ΔSTAT/LoxP) activation. This strategy allowed us to the role of or signaling in hepatocytes and to their during conditions. thus used these animal strains to characterize the of gp130-dependent signaling during liver regeneration after partial and of mice were generated mice with mice gp130 mice expression were used as control animals were generated gp130LoxP/LoxP with knock-in mice a gp130 knock-in that the essential the of gp130 required for activation of and signaling M. M. P. S. U. J. 2001; PubMed Scopus Google Scholar). animals were generated gp130LoxP/LoxP with knock-in The mice a gp130 with a M. M. P. S. U. J. 2001; PubMed Scopus Google Scholar). of the animals and the were of of The were for and the as C. T. U. T. Rose-John S. Muller M. Manns M.P. M. Trautwein C. J. 2005; PubMed Scopus Google Scholar). and LPS mice were used for PH and LPS injury the hepatocyte-specific in PH and were as earlier (13Wuestefeld T. Klein C. Streetz K.L. Betz U. Lauber J. Buer J. Manns M.P. Muller W. Trautwein C. J. Biol. Chem. 2003; 278: 11281-11288Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). The mice were to injury induced of LPS after The mice to LPS challenge in the of PH of LPS. animals were with of The remaining livers were in and in and The of hepatocytes were and as earlier A. U. L. C. A. M. Klein C. Trautwein C. Gastroenterology. Full Text Full Text PDF PubMed Scopus Google Scholar). was with oncostatin M IL-6, and For of DNA synthesis was the and cell proteins and were and liver were in as earlier N. M. J. M. 2005; PubMed Scopus Google and in in was For primary the were with A kinase and As a and were The were using the and in of cells in 5-bromo-2′-deoxyuridine was the animals were were to the cell proliferation cells were with For of the of hepatocytes liver four were the of mice were from liver was and with synthesis as earlier A. U. L. C. A. M. Klein C. Trautwein C. Gastroenterology. Full Text Full Text PDF PubMed Scopus Google Scholar). was using a and The were as and and and and reverse and and The expression were with the of The of was and of was the kinase Liver was with to of were to and for and were for of The were of and for For of the proteins the A were was after the using T. T. Trautwein C. 2001; PubMed Scopus Google Scholar). in in gp130 after is an important mediator of liver regeneration (8Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Crossref PubMed Scopus (1291) Google Scholar). IL-6 via gp130 triggers pathways that are important in mediating protection after PH but has a role in directly mediating hepatocyte proliferation (13Wuestefeld T. Klein C. Streetz K.L. Betz U. Lauber J. Buer J. Manns M.P. Muller W. Trautwein C. J. Biol. Chem. 2003; 278: 11281-11288Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). In present study we the role of gp130-dependent pathways in hepatocytes to their during liver regeneration after PH. used hepatocyte-specific gp130 mice that have a deletion of gp130 in hepatocytes (AlfpCre gp130LoxP/LoxP) or activate the (AlfpCre gp130Y757F/LoxP) or (AlfpCre gp130ΔSTAT/LoxP) pathway in hepatocytes C. T. U. T. Rose-John S. Muller M. Manns M.P. M. Trautwein C. J. 2005; PubMed Scopus Google Scholar). Additionally, gp130 mice were These animals but sites in the gp130 and thus were used as wild type control First, we the regulation of gp130-dependent pathways in these four animal strains PH. of the major acute phase serum amyloid A showed a on the in mice after PH. This regulation was blocked in gp130LoxP/LoxP and In with mice a stronger of was in animals after PH SOCS3 is as a negative of signaling and has an important role during liver regeneration L. W. S. L. L. Immunity. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, R. B. S. H. B. 2005; PubMed Scopus Google Scholar). after PH SOCS3 was induced in animals and in mice with whereas this response was in gp130LoxP/LoxP animals and SOCS3 are STAT3 and its phosphorylation was was in mice after PH, and this signal was enhanced in Additionally, was in gp130LoxP/LoxP and mice of of gp130-dependent on the impact of these on cell cycle progression was A in DNA synthesis was in animals after PH and A was in gp130LoxP/LoxP and In contrast to all mice showed a hepatocytes were after PH, and the of DNA synthesis was after PH A and To better define phase progression, we activation of growth factors like and growth factor. was and after PH in and mice, whereas the in activation was after PH in animals in synthesis was delayed in animals thus hepatocyte proliferation in of the strains showed a in expression after PH. Unexpectedly, expression was in mice with the strains A expression in mice and after PH. In gp130LoxP/LoxP and mice a of A expression was after In gp130LoxP/LoxP animals showed a A expression with animals where of A were to In animals showed delayed A expression with maximal after PH and A expression suggested delayed phase progression in tested J. 1995; PubMed Google Scholar). of after was in all animal strains in mice where maximal was after PH. mice had the the animals, with the strains showed a stronger acute phase response and of SOCS3 associated with of STAT3 that correlated with a in phase progression after PH. in with Higher SOCS3 of PH in mice suggested that the in hepatocyte proliferation correlated with SOCS3 To this we in with primary hepatocytes from or the cells were with either or in with was In mice of in a in DNA synthesis and with IL-6 was associated with proliferation In in mice had major impact on hepatocyte proliferation, whereas DNA synthesis after However, after hepatocyte proliferation in hepatocytes was with all of the not expression in or However, STAT3 phosphorylation in but in cells These in STAT3 activation directly correlated with a SOCS3 expression in hepatocytes LPS after Partial earlier results using gp130 knock-out animals demonstrated that in of cell cycle progression (13Wuestefeld T. Klein C. Streetz K.L. Betz U. Lauber J. Buer J. Manns M.P. Muller W. Trautwein C. J. Biol. Chem. 2003; 278: 11281-11288Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). thus in all strains LPS after PH and DNA synthesis via In all strains the in cells after PH In and animals, a of hepatocytes was In in gp130LoxP/LoxP and animals, of hepatocytes and These results demonstrated a in DNA synthesis after LPS in was the four during the first after PH not A and after PH and LPS in with a the progression of cell cycle in the in expression were A in expression was after in and animals, whereas gp130LoxP/LoxP animals showed expression In mice an with expression was and after and mice In all four maximal A expression was after However, A expression was in and In gp130LoxP/LoxP animals expression the whereas in mice the expression was present and after a after in mice, and in a activation was the However, in these animals an stronger was after were in and gp130LoxP/LoxP was after in gp130LoxP/LoxP In contrast to the mice showed an earlier after PH. these results suggested that LPS the of DNA synthesis in all four mice Additionally, of signaling DNA in the after PH and LPS pathways via that are involved in regulating the acute phase we first expression in the four A with a after was after in animals expression was and with animals with PH In gp130LoxP/LoxP animals in expression was during the first after PH LPS However, in mice after a of was This response was delayed as after in contrast to animals, of was expression during the first showed a with that of a expression to when a of was with the in the was and after and this was stronger with the PH In gp130LoxP/LoxP animals, expression was whereas in mice was after This regulation was with the that were in the PH In animals after STAT3 phosphorylation was after and in contrast to the strains In animals the of SOCS3 expression showed a after and after this and to after The SOCS3 was not with the results of mice in the PH SOCS3 expression in gp130LoxP/LoxP animals was induced after PH. of SOCS3 expression in and mice was during the first after PH, whereas SOCS3 in The of SOCS3 was in expression was with a with after the expression high and to the in we STAT3 phosphorylation in mice after which was not after PH In these animals is expression of the receptor on of the IL-6 signal with gp130 receptor and a second molecule C. S. T. C. R. F. Heinrich P.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the receptor with receptor and after activate STAT3 in we expression of IL-6 of from liver was for the IL-6 and This demonstrated expression in mice to combined challenge of PH and LPS. expression was in and animals after after challenge was in animals and in regulation was in the two signaling was associated with the of after and this response was when gp130-dependent STAT signaling was To characterize this regulation we expression in animals after PH or LPS PH regulation with animals was after PH in mice whereas IL-6 not LPS phosphorylated STAT3 expression was in and mice and after expression of was after LPS in and However, expression in animals was with gp130LoxP/LoxP mice STAT3 and SOCS3 were in and mice, in contrast to gp130LoxP/LoxP of in Phosphorylation of STAT3 in and primary hepatocytes from livers of and mice were with expression was in hepatocytes and after In this response was blocked in gp130LoxP/LoxP animals but was in IL-6 is involved in hepatocyte proliferation and cell protection after PH W. Liang X. Kellendonk C. Poli V. Taub R. J. Biol. Chem. 2002; 277: 28411-28417Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 11Streetz K.L. Luedde T. Manns M.P. Trautwein C. Gut. 2000; 47: 309-312Crossref PubMed Scopus (190) Google Scholar, T. Klein C. Streetz K.L. Betz U. Lauber J. Buer J. Manns M.P. Muller W. Trautwein C. J. Biol. Chem. 2003; 278: 11281-11288Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). IL-6 activates intracellular pathways via the signal transducer and its dimerization results in phosphorylation of tyrosine residues the intracellular of the receptor M. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the present study was to the role of distinct gp130-dependent pathways in hepatocytes during liver two major pathways to Ras/Erk or activation are To these two pathways in hepatocytes they were gp130 knock-in mice with gp130 knock-out this approach we are to gp130-dependent in hepatocytes and the to the strains major in acute phase gene (APG) regulation were after PH. In APG was after PH. This regulation was blocked in animals that gp130-dependent STAT3 activation in In APG expression was enhanced in Additionally, SOCS3 were strongly SOCS3 is a STAT3 gene and via the second phosphorylated gp130 tyrosine activation of gp130-dependent signaling pathways, including activation of STAT3 U. C. U. F. Heinrich P.C. S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). this is blocked in animals, STAT3 phosphorylation and SOCS3 were Unexpectedly, this response was associated with a of hepatocyte proliferation after liver A of cell cycle demonstrated that phase was delayed in these To the we tested activation. is through growth factors like and growth factor that are involved in cell cycle progression of hepatocytes R. B. S. H. B. 2005; PubMed Scopus Google Scholar, Biol. 2001; PubMed Scopus Google Scholar, S. K. Y. H. K. Y. Y. X. M. H. L. S. A. M. K. J. Immunol. 2005; PubMed Scopus Google Scholar, S. K. K. Y. Y. Y. X. M. L. A. K. 2005; PubMed Scopus Google Scholar, L. L. A. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). This that in the gp130 animals, activation was delayed with the SOCS3 regulation is not linked to and earlier results SOCS3 as a negative of and growth factor signaling R. B. S. H. 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To this primary hepatocytes were with or in an in DNA synthesis of primary hepatocytes, which was with IL-6 In in hepatocytes the impact of on DNA synthesis was and IL-6 DNA synthesis after DNA synthesis in these animals correlated with SOCS3 in and in that the of SOCS3 expression involved in DNA demonstrated of IL-6 on cell cycle progression but a role during and after PH (13Wuestefeld T. Klein C. Streetz K.L. Betz U. Lauber J. Buer J. Manns M.P. Muller W. Trautwein C. J. Biol. Chem. 2003; 278: 11281-11288Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, A. X. R. L. 2003; PubMed Scopus Google Scholar, M. R. M. C. H. H. Poli V. Ciliberto G. A. 1998; PubMed Scopus Google Scholar). In earlier study we used MxCre gp130 animals and the These mice have a gp130 In in the present study we the of gp130-dependent signaling in In all strains LPS delayed DNA synthesis to after PH, and major in APG regulation were In contrast to the PH animals, expression was in mice, whereas was in gp130 mice, PH and LPS These results that the acute phase in mice is via gp130 in hepatocytes, whereas factors like LPS or tumor necrosis factor have In mice after were with the In the of SOCS3 until after In these animals, the of DNA synthesis was not delayed and was after with the PH and the in primary hepatocytes, these results that the timing of SOCS3 expression is involved in the of the phase after whereas expression with the of DNA These results are with the that SOCS3 has an impact on the timing of DNA synthesis most with growth signaling R. B. S. H. B. 2005; PubMed Scopus Google Scholar, Biol. 2001; PubMed Scopus Google Scholar, S. K. Y. H. K. Y. Y. X. M. H. L. S. A. M. K. J. Immunol. 2005; PubMed Scopus Google Scholar, S. K. K. Y. Y. Y. X. M. L. A. K. 2005; PubMed Scopus Google Scholar, L. L. A. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). In earlier study using MxCre gp130LoxP/LoxP mice, with gp130 deletion in most of the animals died after challenge M. R. M. C. H. H. Poli V. Ciliberto G. A. 1998; PubMed Scopus Google Scholar). In gp130LoxP/LoxP animals the These results that cells hepatocytes have a major impact on after However, these with present study where gp130LoxP/LoxP mice showed a in hepatocyte proliferation the protective role of IL-6 during liver regeneration. To the of gp130-dependent in we are knock-out mice to their during liver regeneration. mice a gp130 receptor in hepatocytes that the docking sites required for STAT activation. IL-6 after PH was to APG However, the of LPS and SOCS3 expression in these APG were not with This to the that LPS triggers expression of IL-6 that the gp130 receptor in a receptor capacity for STAT3 The of signaling during liver regeneration has been K. H. H. M. A. 2004; PubMed Scopus Google Scholar). showed expression in mice after is a of the Ras/Erk and STAT and in is induced bacterial T. K. A. K. K. Y. K. H. H. 2002; PubMed Scopus Google Scholar). This mice showed stronger DNA synthesis with gp130LoxP/LoxP animals after it is that that gp130 the of IL-6-dependent of activation in these To characterize the role of in mice for STAT3 and APG we these animals with LPS. As after LPS induced expression stronger in these animals with the two control Additionally, in animals, in contrast to was associated with and APG The of a gp130 receptor complex for signaling was in primary gp130 these results suggested that was to a of IL-6 signaling during liver regeneration in these In summary, results that gp130-dependent STAT signaling during liver regeneration in hepatocytes via SOCS3 the timing of phase protective that are important to hepatocyte proliferation during stress conditions. Additionally, the of IL-6-dependent signaling during liver regeneration.