Interleukin-6/Glycoprotein 130-dependent Pathways Are Protective during Liver Regeneration

Abstract

After tissue loss the liver has the unique capacity to restore its mass by hepatocyte proliferation. Interleukin-6 (IL6)-deficient mice show a lack in DNA synthesis after partial hepatectomy (PH). To define better the role of IL6 and its family members for liver regeneration after PH, we used conditional knockout mice for glycoprotein 130 (gp130), the common signal transducer of all IL6 family members. We show that gp130-dependent pathways control Stat3 activation after PH. By using gene array analysis, we demonstrate that c-jun, NF-κB, c-myc, and tumor necrosis factor receptor expression is gp130-dependent. However, in gp130-deleted mice only minor effects on cell cycle and on the maximum of DNA synthesis after PH were found compared with controls. As in conditional gp130 animals, the acute phase response was completely abolished, we considered that other means are essential to define the role of gp130-dependent pathways for liver regeneration. LPS stimulation in gp130-deleted and also IL6 −/− animals after PH leads to a significant reduction in survival and DNA synthesis, which was associated with decreased Bcl-xL expression and higher apoptosis in the liver. These results indicate that the phenotype concerning the reduction in DNA synthesis might be linked to the degree of infection after PH. Thus our results suggest that the role of gp130-dependent signaling is not a direct influence on cell cycle progression after partial hepatectomy but is to activate protective pathways important to enable hepatocyte proliferation. After tissue loss the liver has the unique capacity to restore its mass by hepatocyte proliferation. Interleukin-6 (IL6)-deficient mice show a lack in DNA synthesis after partial hepatectomy (PH). To define better the role of IL6 and its family members for liver regeneration after PH, we used conditional knockout mice for glycoprotein 130 (gp130), the common signal transducer of all IL6 family members. We show that gp130-dependent pathways control Stat3 activation after PH. By using gene array analysis, we demonstrate that c-jun, NF-κB, c-myc, and tumor necrosis factor receptor expression is gp130-dependent. However, in gp130-deleted mice only minor effects on cell cycle and on the maximum of DNA synthesis after PH were found compared with controls. As in conditional gp130 animals, the acute phase response was completely abolished, we considered that other means are essential to define the role of gp130-dependent pathways for liver regeneration. LPS stimulation in gp130-deleted and also IL6 −/− animals after PH leads to a significant reduction in survival and DNA synthesis, which was associated with decreased Bcl-xL expression and higher apoptosis in the liver. These results indicate that the phenotype concerning the reduction in DNA synthesis might be linked to the degree of infection after PH. Thus our results suggest that the role of gp130-dependent signaling is not a direct influence on cell cycle progression after partial hepatectomy but is to activate protective pathways important to enable hepatocyte proliferation. interleukin-6 partial hepatectomy glycoprotein 130 tumor necrosis factor TNF receptor 1 bromodeoxyuridine TdT-mediated dUTP nick end labeling lipopolysaccharide reverse transcriptase glyceraldehyde-3-phosphate dehydrogenase electrophoretic mobility shift assay 4-morpholinepropanesulfonic acid Interleukin 6 (IL6)1belongs to a family comprising of IL6, IL11, leukemia inhibitory factor, oncostatin M, ciliary neurotropic factor, and cardiotropin 1. They all need the gp130 molecule for signal transduction (1Taga T. Kishimoto T. Annu. Rev. Immunol. 1997; 15: 797-819Google Scholar, 2Heinrich P.C. Behrmann I. Muller-Newen G. Schaper F. Graeve L. Biochem. J. 1998; 334: 297-314Google Scholar). Knockout mice with deletion of individual cytokines of the IL6 family have a rather mild phenotype (3Ernst M. Inglese M. Waring P. Campbell I.K. Bao S. Clay F.J. Alexander W.S. Wicks I.P. Tarlinton D.M. Novak U. Heath J.K. Dunn A.R. J. Exp. Med. 2001; 194: 189-204Google Scholar). Experiments elucidating the role of one specific cytokine of the IL6 family during different pathophysiological conditions are thus hampered by a potential redundancy in activity by another family member. Because all known IL6 family members use gp130 for signal transduction, mice lacking functional gp130 are an attractive model to study the role of IL6-related pathways in vivo. gp130 knockout mice die in uteri or directly after birth due to myocardial hypoplasia and reduced hemopoiesis in the fetal liver (4Yoshida K. Taga T. Saito M. Suematsu S. Kumanogoh A. Tanaka T. Fujiwara H. Hirata M. Yamagami T. Nakahata T. Hirabayashi T. Yoneda Y. Tanaka K. Wang W.Z. Mori C. Shiota K. Yoshida N. Kishimoto T. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 407-411Google Scholar,5Kawasaki K. Gao Y.H. Yokose S. Kaji Y. Nakamura T. Suda T. Yoshida K. Taga T. Kishimoto T. Kataoka H. Yuasa T. Norimatsu H. Yamaguchi A. Endocrinology. 1997; 138: 4959-4965Google Scholar). In order to circumvent this problem, conditional gp130 knockout mice using the Cre/loxP system were generated (6Betz U.A. Bloch W. van den Broek M. Yoshida K. Taga T. Kishimoto T. Addicks K. Rajewsky K. Muller W. J. Exp. Med. 1998; 188: 1955-1965Google Scholar). In these mice exon 16 coding for the gp130 transmembrane domain can be deleted as two loxP sites flank it. In animals with the Cre recombinase under the control of the Mx promoter, expression is induced by interferon-α or agents triggering internal interferon-α expression, e.g. pIpC (6Betz U.A. Bloch W. van den Broek M. Yoshida K. Taga T. Kishimoto T. Addicks K. Rajewsky K. Muller W. J. Exp. Med. 1998; 188: 1955-1965Google Scholar,7Kühn R. Schwenk F. Aguet M. Rajewsky K. Science. 1995; 269: 1427-1429Google Scholar). In the liver, IL6 is a major regulator of the acute phase response. It has also been shown that IL6 is essential for liver regeneration after partial hepatectomy (PH) (8Trautwein C. Rakemann T. Niehof M. Rose-John S. Manns M.P. Gastroenterology. 1996; 110: 1854-1862Google Scholar, 9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar). First experiments indicated that there is an elevation of TNFα followed by IL6 in the serum of animals after PH (8Trautwein C. Rakemann T. Niehof M. Rose-John S. Manns M.P. Gastroenterology. 1996; 110: 1854-1862Google Scholar). Further studies using IL6 and TNF receptor 1 (TNF-R1) knockout mice (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar, 10Yamada Y. Kirillova I. Peschon J.J. Fausto N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1441-1446Google Scholar) demonstrated that in both knockout animals S phase progression is impaired and some of the animals die after surgery. In both IL6 and TNF-R1 knockout mice, the defect in hepatocyte proliferation can be rescued by treating the animals with IL6. These results imply that the increase in TNFα levels is important to induce IL6, which is ultimately involved in triggering liver regeneration (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar,11Streetz K.L. Luedde T. Manns M.P. Trautwein C. Gut. 2000; 47: 309-312Google Scholar). However, other reports indicated the possibility that the role of IL6 on cell cycle progression during liver regeneration after PH is less essential as hypothesized previously (12Sakamoto T. Liu Z. Murase N. Ezure T. Yokomuro S. Poli V. Demetris A.J. Hepatology. 1999; 29: 403-411Google Scholar). These results suggest the possibility that other factors, e.g. the expression of other IL6 family members, may modulate the outcome after PH and raise the question of the ultimate role of IL6 during liver regeneration. In order to circumvent a possible redundancy of different IL6 family members, we used conditional gp130 knockout mice to study liver regeneration after PH. By using this approach, we define more precisely the role of IL6/gp130-dependent signaling, and we show that these pathways may determine survival after PH but not the expression of genes directly involved in cell cycle control. gp130 loxP (+/+) Mx-Cre(−) mice were bred with gp130 loxP (+/+) Mx-Cre(+) animals. By using this approach, littermates were always homozygote for gp130 loxP and had a 50% chance for the Mx-Cre transgene. These animals with identical backgrounds were then used for further experiments. Cre+ and Cre− (controls) animals were always treated in parallel with pIpC (Sigma) as indicated. 30 μg of isolated genomic DNA derived from mouse livers was digested with EcoRI overnight, separated on a 1% agarose gel, and transferred to Hybond N+ membranes. Membranes were with a gp130 as (6Betz U.A. Bloch W. van den Broek M. Yoshida K. Taga T. Kishimoto T. Addicks K. Rajewsky K. Muller W. J. Exp. Med. 1998; 188: 1955-1965Google Scholar). deletion in other has been (6Betz U.A. Bloch W. van den Broek M. Yoshida K. Taga T. Kishimoto T. Addicks K. Rajewsky K. Muller W. J. Exp. Med. 1998; 188: 1955-1965Google Scholar). IL6 knockout and were used in this U. Biochem. J. 1997; Scholar, M. H. G. M. M. Kishimoto T. R. H. G. Scholar). IL6 −/− was a of of and was to a U. S. IL6 −/− U. Biochem. J. 1997; Scholar) was from of and and animals were with μg of different after stimulation these animals were treated with μg of IL6 after IL6 the liver was and liver were as C. Rakemann T. J. G. Manns M.P. J. 1998; Scholar). assay using the mouse IL6 IL6 serum gp130 and (controls) animals were treated with μg of pIpC after stimulation and was from the animals. hepatectomy was as T. Rakemann T. S. Manns M.P. Trautwein C. Hepatology. 2000; Scholar). and liver were for the of exon 16 deletion by In all mice the in the liver was LPS stimulation experiments 30 μg of mouse (Sigma) was after partial indicated mice were used in was from the animals livers were and in and of the livers were in or liver was used to C. Rakemann T. J. G. Manns M.P. J. 1998; Scholar). were separated on a and a as previously C. Rakemann T. J. G. Manns M.P. J. 1998; and was Membranes were with and as As a was were using the system as by the was for of derived from different animals. shift experiments were as previously C. Rakemann T. J. G. Manns M.P. J. 1998; Scholar). were with a Stat3 and in 1 serum μg of liver was for 30 on DNA and were on a experiments were using and in 30 mice, was tissue was in were in and to the cell proliferation was as to T. S. J. C. Manns M.P. Trautwein C. 2001; Scholar). serum c-myc, and were with to the for was as previously T. S. J. C. Manns M.P. Trautwein C. 2001; Scholar). were for and to an for specific were to the and to 1 for animals. for expression livers from were in for and of was and treated with to the and the of μg of was by from from of the were to mouse expression μg of was with and to to the were to expression using with After two the were to a results were by using of was from the generated by was dUTP nick end was using the from to the of the were with a was isolated as previously T. S. J. C. Manns M.P. Trautwein C. 2001; Scholar). First synthesis for was using and the in with 1 μg of of Bcl-xL and was in one using the specific and and and 1 of the was for with DNA and Bcl-xL a of the was for were and the was for another were and using a and direct the was of results was with a and as T. Rakemann T. S. Manns M.P. Trautwein C. Hepatology. 2000; Scholar). pIpC interferon-α expression in the Mx R. Schwenk F. Aguet M. Rajewsky K. Science. 1995; 269: 1427-1429Google Scholar, T. G. C. Poli V. 2001; Scholar). We of pIpC in animals and to deletion of gp130 exon 16 in the liver. after pIpC the liver of the animals was and DNA was As by analysis, μg of pIpC in a more deletion of exon 16 in the gp130 in Mx-Cre and not animals not μg and higher and not of pIpC more of exon 16 was deleted in animals. we the functional of a deletion higher of gp130 exon 16 after μg of pIpC in the liver. gp130 loxP animals were with μg of for different after pIpC shift with a Stat3 that Stat3 was completely after pIpC not results using IL6 knockout mice that IL6 is involved in cell cycle progression after PH (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar). We partial in conditional gp130 knockout gp130 loxP to as and gp130 loxP (controls) animals were both treated with μg of After PH was indicated animals were and the of gp130 exon 16 deletion was by in the liver further only mice were with a deletion We IL6 serum In both IL6 serum levels after PH 1 In IL6 expression was found after 6 and in the gp130-deleted after IL6 levels were more higher in the gp130-deleted and the was compared with 1 the two there was in after PH. experiments Stat3 1 after PH in the control decreased and to levels 1 In gp130-deleted animals Stat3 activation after PH was completely increase in was found compared with the 1 of cytokine signaling is a of gene study by L. Schaper F. J. A. P.C. Fausto N. J. 2001; Scholar) a of liver regeneration. we expression in both were and 6 after PH in the control was found in gp130-deleted animals 1 significant was found both after PH not gp130-dependent signaling was in gp130-deleted mice after PH. In further experiments we the on DNA synthesis after PH by experiments in both In the control a maximum of was after PH. of all were and In gp130-deleted animals the maximum of was after PH and was compared with controls. of all were in gp130-deleted animals. the of decreased and In further experiments we the of gp130 deletion on expression after PH. and expression was by experiments. In control animals expression was after PH. was a increase in expression for to expression decreased In gp130-deleted animals, was only after PH, and a increase was to after PH. expression expression in was after PH and decreased in gp130-deleted animals expression was the and experiments more in cell cycle progression after hepatectomy in IL6 knockout animals compared with (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar, T. Liu Z. Murase N. Ezure T. Yokomuro S. Poli V. Demetris A.J. Hepatology. 1999; 29: 403-411Google Scholar). we for specific pathways to IL6 may influence cell cycle progression in the liver. We gp130-deleted and control mice with IL6 for 6 and of and animals were used for gene array of this was on genes that are involved in cell cycle control. two and c-myc, that might have an on phase and are in an in the liver on genes directly involved in cell cycle was gene array also a on the expression of the gp130-deleted animals are in the In further experiments we to our gene array by expression by and after PH. expression and the after PH as found in were reduced in gp130-deleted animals. Thus gp130-dependent pathways to the and expression after PH not is a of the after PH was by shift experiments using a was after PH in controls. decreased and was reduced to levels In the gp130-deleted animals specific was only after hepatectomy and after PH In to has been shown also for that its activation with liver regeneration after PH C. Fausto N. Scholar, D.E. Greenbaum L.E. Taub R. J. 269: Scholar). In activation was and after PH In gp130-deleted mice the of activation was the be to experiments in the gp130-deleted animals indicated that gp130-dependent pathways are essential for liver in to the activation of genes as shown previously (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar). Because in our experiments the on DNA synthesis was less after PH as in IL6 −/− mice (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google we partial in IL6 knockout animals U. Biochem. J. 1997; Scholar) and DNA synthesis was in after PH. levels were found after PH. after PH the of decreased with in IL6 −/− animals the increase and maximum in DNA synthesis was reduced and As may for in hepatocyte we in a IL6 −/− M. H. G. M. M. Kishimoto T. R. H. G. Scholar) and for These results were with the in the IL6 −/− not IL6 to acute phase gene expression and a of after C. K. Manns M.P. Gut. Scholar). Thus after the outcome may the of the liver to control In further experiments the on acute phase gene expression was in gp130-deleted As shown in serum and gene expression were and levels were after PH in controls. In this increase in acute phase gene expression after PH was not found in gp130-deleted mice 6 expression decreased after PH in the control 6 In gp130-deleted animals only minor in levels were in the 6 These results demonstrate that after PH of the acute phase response is in gp130-deleted animals. As of the acute phase response was impaired in gp130-deleted animals, we the of a by LPS on liver regeneration. LPS was after PH, and the on survival and DNA synthesis was gp130-deleted animals had a outcome compared with controls. In the gp130-deleted of the animals during the after PH. In the survival in was after LPS 6 with a in DNA synthesis in gp130-deleted animals after an of in gp130-deleted animals compared with 6 As LPS had a significant on survival and DNA synthesis of gp130-deleted animals, we also the of LPS on survival in IL6 knockout animals compared with IL6 −/− animals and were treated with LPS after PH. was in the after PH. In the IL6 −/− animals more animals after PH were treated with LPS compared with and animals. Thus as found in the gp130-deleted animals, IL6 −/− mice were more to LPS after PH These were also was in the liver of these animals. DNA synthesis after PH in IL6 −/− mice was reduced compared with experiments indicated that protective might be impaired in gp130-deleted animals. experiments that IL6 might pathways by higher K. W. DeAngelis R. Greenbaum L.E. Ciliberto G. Taub R. J. 2001; Scholar). we an after PH. In control animals we found an increase in Bcl-xL expression after PH which was not found in gp130-deleted animals and As in Bcl-xL might be one of the gp130-dependent from apoptosis after LPS we there is a in the degree of apoptosis and gp130-deleted animals. the PH we found a significant increase in apoptosis in the gp130-deleted animals compared with In gp130-deleted mice more liver were compared with essential to restore liver mass after are and the and pathways that liver regeneration have on a K.L. Luedde T. Manns M.P. Trautwein C. Gut. 2000; 47: 309-312Google Scholar, N. J. 1995; Scholar, Science. 1997; Scholar). experiments that after partial hepatectomy there is activation of Stat3 in the after (8Trautwein C. Rakemann T. Niehof M. Rose-John S. Manns M.P. Gastroenterology. 1996; 110: 1854-1862Google Scholar, D.E. Taub R. Hepatology. 1995; Scholar). Further experiments using IL6 knockout mice demonstrated that this cytokine is involved in the response after PH (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar). TNF-R1 knockout mice a lack in liver regeneration that be rescued by IL6 Y. Kirillova I. Peschon J.J. Fausto N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1441-1446Google Scholar). on these a model has been TNFα and then IL6 serum levels are and the pathways that are these two cytokines are essential to cell cycle progression after PH. In the study we were to further the role of IL6 for liver regeneration after partial hepatectomy using conditional gp130 knockout After birth Cre expression in animals was induced by pIpC experiments demonstrated that in these animals deletion of gp130 exon 16 was in the liver and other tissue to the response (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar). In the liver more of exon 16 in the gp130 was and Stat3 activation was in to controls. of the IL6 family members need gp130 for signal transduction, and thus the use of gp130 animals the possibility that other cytokines of this family may for the loss of other (1Taga T. Kishimoto T. Annu. Rev. Immunol. 1997; 15: 797-819Google P.C. Behrmann I. Muller-Newen G. Schaper F. Graeve L. Biochem. J. 1998; 334: 297-314Google Scholar). After PH in of the control Stat3 activation was to the after PH, IL6 serum levels were found after 6 experiments by Fausto and L. Schaper F. J. A. P.C. Fausto N. J. 2001; Scholar) have a for this They demonstrated that only 1 after partial hepatectomy is induced on the and maximum expression after In the we further this and that gp130-dependent pathways in expression Stat3 activation is after PH. In our study there is a the activation of Stat3 after partial hepatectomy and the of IL6 serum As in the gp130-deleted animals Stat3 DNA was and activation is to be a gp130-dependent in IL6 −/− animals Stat3 activation was found after PH (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar). These two indicate that IL6 Stat3 after PH. is that IL6 levels are in the liver after PH as the cytokine this may to in the liver are and IL6 levels are in the serum of the animals. In the serum IL6 is to and gp130 that the activation of gp130-dependent pathways also in liver As the of gp130 is in the gp130-deleted animals, IL6 has a in the serum of these animals. regeneration in gp130-deleted animals compared with controls. Stat3 activation was completely and gene array gp130-dependent and c-jun, after PH. our experiments suggest that activation the during liver regeneration is gp130-dependent. for and activation after partial hepatectomy might be on different However, our gene array also the expression of both is IL6 as in gp130-deleted animals the and the expression of TNF-R1 and the expression of are reduced As and are TNF after PH, these results in a reduction in the activation of both in the gp130-deleted animals after PH. is in and reports of Taub and (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar) and Fausto and Y. Kirillova I. Peschon J.J. Fausto N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1441-1446Google Scholar) that activation of genes is on IL6 after PH (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar, 10Yamada Y. Kirillova I. Peschon J.J. Fausto N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1441-1446Google Scholar). However, DNA synthesis was reduced in conditional gp130 knockout animals but less impaired as previously in IL6 −/− animals. increase in and expression was in gp130-deleted animals, which was associated with a minor reduction in DNA synthesis after PH. array significant of IL6 on genes directly involved in cell cycle control. results were also in IL6 −/− mice using gene array after PH W. K. Ciliberto G. Taub R. Hepatology. 2001; Scholar). the gp130-deleted animals restore liver mass and had compared with controls. the reduction of gene activation in gp130-deleted mice that in the liver pathways to induce hepatocyte proliferation. was However, further of the IL6 −/− experiments of (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar) that IL6 −/− animals that the after hepatectomy had a liver after These results imply that IL6 is important but not in order to restore liver mass after PH. there be that some of the IL6 −/− animals and completely liver is further by the of and (12Sakamoto T. Liu Z. Murase N. Ezure T. Yokomuro S. Poli V. Demetris A.J. Hepatology. 1999; 29: 403-411Google Scholar) using IL6 −/− They demonstrated that in IL6 −/− mice the reduction in DNA synthesis after PH is less as by (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar) and was with the degree of reduction in DNA synthesis in our experiments. In our reports we used a mouse that the IL6 receptor under the control of a control In these animals IL6 gp130-dependent signaling in In to our PH and IL6 stimulation not in an increase of hepatocyte proliferation but to a in cell cycle Thus of gp130-dependent pathways in was not associated with DNA in the results of different in the IL6 and hepatocyte proliferation was Thus was to ultimately define the role of IL6 and thus of gp130-dependent for liver regeneration. we considered other means to the role of IL6 for cell cycle progression after PH. studies K. W. DeAngelis R. Greenbaum L.E. Ciliberto G. Taub R. J. 2001; Scholar, M. Rose-John S. J. 2000; Scholar, M. Hepatology. 1999; Scholar) demonstrated that IL6 e.g. pathways in These results to the possibility that the role of IL6 in the liver after PH is not to cell cycle progression genes but is to the liver from during this We show in our study that in gp130-deleted animals acute phase gene and thus are after PH. to a we LPS in gp130-deleted and control animals after PH. These experiments in the outcome of these animals to the results in the PH experiments in the IL6 −/− animals (9Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Google Scholar). After PH DNA synthesis was reduced in the gp130-deleted animals, and the phenotype was found LPS was IL6 −/− mice after PH. with this gp130 knockout animals are also to LPS that gp130-dependent pathways in are essential for this K. T. A. K. F. U. Muller W. Manns M. Trautwein C. Hepatology. 2001; Scholar). In further experiments we the possible that might for higher LPS As in experiments K. W. DeAngelis R. Greenbaum L.E. Ciliberto G. Taub R. J. 2001; Scholar) that IL6 and we its expression by and found expression in the gp130-deleted animals. After PH the with a higher of apoptosis in the gp130-deleted animals after LPS stimulation that this is an important that to the outcome in these animals after partial hepatectomy and LPS on these results we define more the role of the IL6/gp130-dependent during liver regeneration. IL6 expression after PH is important to activate protective pathways that more e.g. after PH. results suggest that the phenotype of gp130-deleted and IL6 knockout animals after PH is to the degree of These results there are in the the of the phenotype in IL6 −/− mice after partial