CCAAT Enhancer-binding Protein α Is Required for Interleukin-6 Receptor α Signaling in Newborn Hepatocytes

The acute phase response is an evolutionarily conserved response of the liver to inflammatory stimuli, which aids the body in host defense and homeostasis. We have previously reported that CCAAT enhancer-binding protein α (C/EBPα) is required for the induction of acute phase protein (APP) genes in newborn mice in response to lipopolysaccharide. In this paper, we describe a mechanism by which C/EBPα knock-out mice are unable to induce APP gene expression in response to inflammatory stimuli. We demonstrate that the lack of acute phase response in C/EBPα knock-out mice is because of a hepatocyte autonomous defect. C/EBPα knock-out hepatocytes do not activate STAT3 in response to recombinant interleukin (IL)-6, indicating a defect in the IL-6 pathway. C/EBPα knock-out hepatocytes also do not show activation of other IL-6 receptor (IL-6R)-mediated Janus kinase substrates, gp130, SHP-2, and Tyk2. Further examination of the IL-6 pathway demonstrated that C/EBPα knock-out hepatocytes have decreased IL-6Rα protein levels caused, in part, by reduced protein stability. However, other components of the IL-6 pathway are intact, as demonstrated by rescue of STAT3 activation and APP gene induction with recombinant-soluble IL-6R linked to IL-6 cytokine (Hyper-IL-6) or with another gp130 signaling cytokine, Oncostatin M. In conclusion, C/EBPα is required for the proper regulation of IL-6Rα protein in hepatocytes resulting in a lack of acute phase protein gene induction in newborn C/EBPα null mice in response to lipopolysaccharide or cytokines. The acute phase response is an evolutionarily conserved response of the liver to inflammatory stimuli, which aids the body in host defense and homeostasis. We have previously reported that CCAAT enhancer-binding protein α (C/EBPα) is required for the induction of acute phase protein (APP) genes in newborn mice in response to lipopolysaccharide. In this paper, we describe a mechanism by which C/EBPα knock-out mice are unable to induce APP gene expression in response to inflammatory stimuli. We demonstrate that the lack of acute phase response in C/EBPα knock-out mice is because of a hepatocyte autonomous defect. C/EBPα knock-out hepatocytes do not activate STAT3 in response to recombinant interleukin (IL)-6, indicating a defect in the IL-6 pathway. C/EBPα knock-out hepatocytes also do not show activation of other IL-6 receptor (IL-6R)-mediated Janus kinase substrates, gp130, SHP-2, and Tyk2. Further examination of the IL-6 pathway demonstrated that C/EBPα knock-out hepatocytes have decreased IL-6Rα protein levels caused, in part, by reduced protein stability. However, other components of the IL-6 pathway are intact, as demonstrated by rescue of STAT3 activation and APP gene induction with recombinant-soluble IL-6R linked to IL-6 cytokine (Hyper-IL-6) or with another gp130 signaling cytokine, Oncostatin M. In conclusion, C/EBPα is required for the proper regulation of IL-6Rα protein in hepatocytes resulting in a lack of acute phase protein gene induction in newborn C/EBPα null mice in response to lipopolysaccharide or cytokines. The acute phase response (APR) 1The abbreviations used are: APR, acute phase response; APP, acute phase protein; IL, interleukin; C/EBP, CCAAT enhancer-binding protein α; KO, knock-out; STAT, signal transducers and activators of transcription; JAK, Janus kinase; WT, wild type; IL-6R, IL-6 receptor; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; TNF-α, tumor necrosis factor-α; RIPA, radioimmune precipitation assay; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; RT, reverse transcriptase; EMSA, electrophoretic mobility shift assay; OncM, Oncostatin M; OncMR, OncM receptor. is the rapid systemic response by the body to inflammatory stimuli such as tissue damage or infection. At the site of damage, macrophages and other surrounding cells detect injury and respond by secreting pro-inflammatory cytokines including IL-1, IL-6, and TNF-α into the blood stream to elicit a systemic response. The liver is highly responsive to these cytokines because of the high density of cytokine receptors on hepatocytes. These cytokines evoke changes in expression of acute phase protein (APP) genes, such as positively regulated APP genes like serum amyloid A (SAA), γ-fibrinogen, and haptoglobin and negatively regulated APP genes like albumin and transferrin. These acute phase proteins are made by hepatocytes and then secreted into the blood-stream where they play a variety of roles in homeostasis, host defense, and minimizing tissue damage (see Refs. 1Baumann H. Gauldie J. Immunol. Today. 1994; 15: 74-80Abstract Full Text PDF PubMed Scopus (468) Google Scholar, 2Moshage H. J. Pathol. 1997; 181: 257-266Crossref PubMed Scopus (570) Google Scholar). IL-1, IL-6, and TNF-α signal through known receptors to activate three major transcription factor families: NFκB, C/EBPs, and STATs. These factors regulate APP gene expression at the transcriptional level. IL-1 and TNF-α activate NFκB p50 and p65, which recognize the consensus sites in the promoters of many APP genes such the serum amyloid A gene family (3Li X.X. Liao W.S. J. Biol. Chem. 1991; 266: 15192-15201Abstract Full Text PDF PubMed Google Scholar). IL-6 induces the tyrosine phosphorylation and DNA binding activity of STAT3, which bind fibrinogen and α2-macroglobulin promoters among others (4Zhang Z. Fuentes N.L. Fuller G.M. J. Biol. Chem. 1995; 270: 24287-24291Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 5Zhang X. Darnell Jr., J.E. J. Biol. Chem. 2001; 276: 33576-33581Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). IL-1 and IL-6 induce C/EBPβ and C/EBPδ at both the transcriptional and protein activation levels, whereas C/EBPα is slightly down-regulated (6Ray B.K. Gao X. Ray A. Eur. J. Biochem. 1993; 216: 127-136Crossref PubMed Scopus (8) Google Scholar, 7Alam T. An M.R. Papaconstantinou J. J. Biol. Chem. 1992; 267: 5021-5024Abstract Full Text PDF PubMed Google Scholar). This leads to the replacement of C/EBPα DNA binding at C/EBP sites in promoters of APP genes with C/EBPβ and δ. Previously, it was thought that C/EBPα played a passive role in the APR; however, our laboratory has shown that C/EBPα is required for the induction of many APP genes in mice (8Burgess-Beusse B.L. Darlington G.J. Mol. Cell. Biol. 1998; 18: 7269-7277Crossref PubMed Scopus (65) Google Scholar). Neonatal C/EBPα null mice do not elevate APP genes but do induce NFκB, C/EBPβ, and C/EBPδ DNA binding in response to LPS injection. In contrast, C/EBPα knock-out (KO) mice do not activate STAT3 DNA binding in response to LPS, indicating a defect in the IL-6-STAT3 signaling pathway (8Burgess-Beusse B.L. Darlington G.J. Mol. Cell. Biol. 1998; 18: 7269-7277Crossref PubMed Scopus (65) Google Scholar). IL-6 is thought to be the main stimulator of the induction of APP genes during the hepatic acute phase response, whereas IL-1 and TNF-α influence the expression of subgroups of APP genes and induce IL-6 cytokine production (9Gauldie J. Richards C. Harnish D. Lansdorp P. Baumann H. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 7251-7255Crossref PubMed Scopus (1376) Google Scholar). IL-6 knock-out mice induce APP genes in response to the systemic APR inducer bacterial LPS, whereas the response to a localized tissue damage by turpentine injection does not induce APP gene expression in these mice (10Fattori E. Cappelletti M. Costa P. Sellitto C. Cantoni L. Carelli M. Faggioni R. Fantuzzi P. J. 1994; PubMed Scopus Google Scholar). IL-6 null mice respond to LPS by activation of however, STAT3 is not in response to turpentine T. E. Cappelletti M. 1998; PubMed Scopus Google Scholar). The that other STAT3 such as or Oncostatin be in response to LPS but not to turpentine (10Fattori E. Cappelletti M. Costa P. Sellitto C. Cantoni L. Carelli M. Faggioni R. Fantuzzi P. J. 1994; PubMed Scopus Google Scholar). STAT3 activation by an signaling pathway has shown to be the of APP gene expression in mice through of the STAT3 gene in the liver T. D. C. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). In these STAT3 knock-out APP genes are not in response to LPS genes to be do not have STAT3 binding sites in IL-6 cytokines signal by binding to an which and through of the gp130 signaling The of these receptor in to other to and activation of the including and Tyk2. The activate the pathway through phosphorylation of the SHP-2, to activation of also activate STAT3 by tyrosine and into the where STAT3 bind to sites in the promoters of many APP genes L. Biochem. J. 1998; PubMed Scopus Google Scholar). laboratory has the roles of C/EBPα in C/EBPα is a transcription factor highly in liver and tissue S. J. PubMed Scopus Google Scholar). C/EBPα null mice because of because C/EBPα is in the expression of many genes A. Darlington G.J. 1995; PubMed Scopus Google Scholar). We previously reported that C/EBPα null mice do not respond to LPS by APP genes and do not activate STAT3 DNA binding (8Burgess-Beusse B.L. Darlington G.J. Mol. Cell. Biol. 1998; 18: 7269-7277Crossref PubMed Scopus (65) Google Scholar). However, it was not known the lack of APR in C/EBPα null mice was the of a defect in the hepatocytes or in the signaling of the In this paper, we that C/EBPα null hepatocytes in are unable to respond to recombinant IL-6 to induce APP gene expression and STAT3 DNA The IL-1 pathway is as the gene H. 1994; PubMed Scopus Google is IL-1 of C/EBPα knock-out hepatocytes. we show that STAT3 is not because of in the IL-6R signaling pathway. IL-6Rα protein levels in C/EBPα null hepatocytes are which is in to decreased protein of the receptor. the of the cytokine Oncostatin or the IL-6Rα linked to IL-6, T. M. S. M. S. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google is of STAT3 DNA binding and induction of the acute phase protein in hepatocytes C/EBPα null We that the reduced expression of the IL-6 receptor is for the of C/EBPα knock-out mice to respond to inflammatory stimuli. APR in mice with body of LPS to induce a inflammatory response, and at LPS injection. of the mice with to the in C/EBPα knock-out and newborn C/EBPα and mice and by the liver by at in for by a with and with then in and for at by hepatocytes through a to and tissue in and to for and then cells in to in factor and other and at on of hepatocytes. hepatocytes with of the cytokines used at a of in for the in the IL-1 was Oncostatin and IL-6 was a at was on liver LPS injection and on hepatocyte of cytokine was to was as previously (8Burgess-Beusse B.L. Darlington G.J. Mol. Cell. Biol. 1998; 18: 7269-7277Crossref PubMed Scopus (65) Google Scholar). of was as previously M. B.L. Darlington G.J. Mol. Cell. Biol. 1997; PubMed Google Scholar). tissue or hepatocytes and in a high on for and to used for tissue or hepatocytes in a and by on for was for to STAT3 in binding and of with of and on for was by a at on a at The and of or of on a and was as previously M. B.L. Darlington G.J. Mol. Cell. Biol. 1997; PubMed Google Scholar). STAT3 used at a STAT3 gp130 and IL-6Rα used to show of of liver was with of protein at for proteins a of and for of at of protein to the for and the was for The with and in and the on for was the to of was used to gp130, and levels in hepatocytes. was by was by was as in with the for the with a of the cells with and C/EBPα and hepatocytes with and for in The cells then with of and for then three with and then in of for the made as of was with protein for IL-6Rα was with of IL-6Rα at of protein was for to the protein with in and on the of and hepatocytes with for made at and IL-6Rα protein levels by and a and was to protein levels to the of three C/EBPα and hepatocytes also with or for to for and hepatocyte was the with the in with of was used for reverse transcription and reverse The to by and was used for was the on an used for and reverse and reverse the with to the of of APP during the APR a in C/EBPα C/EBPα null mice are unable to respond to the bacterial LPS and do not induce APP genes, such as and However, we have that IL-1, TNF-α, and IL-6 levels are in both C/EBPα and in response to LPS not to the defect in APP gene induction was because of a systemic defect in the C/EBPα knock-out mice or a defect in the hepatocytes hepatocytes newborn C/EBPα knock-out and wild mice for and with recombinant cytokines IL-1 and IL-6 to the acute phase response or with APP genes in hepatocytes in response to the recombinant cytokine of IL-1 and IL-6 and LPS, whereas C/EBPα hepatocytes in APP expression and levels of are decreased in C/EBPα hepatocytes but in not hepatocytes expression of levels and a induction of the whereas C/EBPα hepatocytes do not induce these However, the which is H. 1994; PubMed Scopus Google is in both and hepatocytes with recombinant IL-1 and IL-6 and with IL-1 not indicating that the IL-1 pathway is in hepatocytes The that the C/EBPα hepatocytes do not respond to the of recombinant IL-6 to elevate APP genes that the hepatocytes lack of this pro-inflammatory signaling pathway. C/EBPα to STAT3 in to IL-6 IL-6 signaling pathway STAT3 DNA binding and tyrosine phosphorylation of We then STAT3, the main transcription factor by IL-6 and in the induction of APP genes, be by LPS or the cytokine in C/EBPα knock-out STAT3 is in liver in response to of LPS in mice as demonstrated by of of the binding with STAT3 However, STAT3 DNA binding is not in C/EBPα knock-out liver in response to LPS In STAT3 DNA binding is at both and whereas C/EBPα null hepatocytes induce or STAT3 DNA binding at The of STAT3 to the binding of STAT3 DNA The of STAT3 binding to a STAT3 is shown by with of liver STAT3 show induction of STAT3 tyrosine phosphorylation in mice in response to LPS whereas C/EBPα liver STAT3 by LPS In hepatocytes induce STAT3 phosphorylation in response to the IL-1 and IL-6 However, C/EBPα hepatocytes STAT3 tyrosine phosphorylation in response to the the IL-6-STAT3 pathway is the major inducer of the hepatic acute phase response, it is that the lack of APP gene induction in C/EBPα mice and hepatocytes is because of a defect in the IL-6-STAT3 signaling in C/EBPα are the family of for the tyrosine phosphorylation of STAT3 in the IL-6 signaling pathway L. Biochem. J. 1998; PubMed Scopus Google we then in response to LPS in C/EBPα We the activation of by the phosphorylation of of gp130 and SHP-2, and a of the family of Tyk2. of proteins tyrosine and of gp130, SHP-2, and of IL-6 receptor demonstrated reduced phosphorylation of these proteins in C/EBPα liver with liver LPS levels of gp130 and in the and are shown in whereas is not at but in both and liver LPS The lack of tyrosine phosphorylation of gp130, SHP-2, and of in C/EBPα liver that the IL-6 pathway is not in response to recombinant IL-6 or C/EBPα and of the C/EBPα hepatocytes do not respond to IL-6 by APP gene or STAT3, expression levels of the IL-6 receptor signaling components of IL-6Rα and gp130 levels on three of hepatocytes C/EBPα and The in A and show the of the levels of IL-6Rα and gp130 as a to a IL-6Rα levels are not and for and the in or IL-1 and IL-6 hepatocytes. 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The IL-6Rα and protein levels in C/EBPα and hepatocytes that the protein is regulated the at the of protein stability. of IL-6Rα in C/EBPα the of of IL-6Rα was C/EBPα and hepatocytes. hepatocytes with and in the of and The of into IL-6Rα protein is not C/EBPα and hepatocytes with and for the and We then decreased protein is for the reduced protein levels in C/EBPα hepatocytes. the of IL-6Rα protein in we a and C/EBPα hepatocytes with and for and with and for the in and C. IL-6Rα was and by of IL-6Rα the to be in C/EBPα hepatocytes with hepatocytes. that C/EBPα hepatocytes have a IL-6Rα protein of the hepatocytes was to protein The of protein of IL-6Rα was a levels of IL-6Rα protein are decreased in C/EBPα to three protein was the C/EBPα hepatocytes to detect IL-6Rα levels by and as a of the levels to show the in protein in The of IL-6Rα in C/EBPα hepatocytes is in C/EBPα hepatocytes. A of IL-6Rα protein levels during the is shown in it is that of are slightly in the with the are to in the because protein and in the hepatocytes. the of on IL-6Rα we the hepatocytes with of the main of protein and an of the and a IL-6Rα protein during in C/EBPα and hepatocytes These that decreased IL-6Rα protein to the decreased IL-6Rα protein in C/EBPα hepatocytes and that both the and of protein are in IL-6Rα protein in hepatocytes. or Oncostatin STAT3 and in C/EBPα gp130 signaling cytokines IL-6 have reported to activate STAT3 DNA binding and induce APP gene expression Fantuzzi S. M. P. Cappelletti M. D. P. PubMed Google Scholar). We then gp130 and the other components of the IL-6 pathway are in C/EBPα the We the response of C/EBPα and hepatocytes to Oncostatin and OncM is an cytokine that through a of and gp130 T. T. Immunol. 1997; 15: PubMed Scopus Google Scholar). is a recombinant protein to have the IL-6Rα linked to the IL-6 cytokine, which through gp130 in a T. M. S. M. S. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). hepatocytes respond to IL-6, and OncM by STAT3 DNA binding C/EBPα hepatocytes do not induce STAT3 DNA binding in response to IL-6 as in this and However, C/EBPα hepatocytes induce STAT3 DNA binding in response to and Oncostatin M. hepatocytes of both induce STAT3 DNA binding in cells with Oncostatin with IL-6 or This in the receptor of and IL-6Rα for the gp130 signaling protein and has previously shown to be by IL-1 and have induction with IL-1 and IL-6 whereas IL-6 is not a inducer of in hepatocytes J. Immunol. PubMed Scopus Google Scholar). The cytokine induction of is a response to because of and high transcriptional induction in response to cytokines. We induction by in and C/EBPα hepatocytes in response to of cytokines. hepatocytes in with previously J. Immunol. PubMed Scopus Google with induction of in response to IL-6, induction with IL-1, and induction in cells with IL-1 and IL-6 a induction of to both cytokines hepatocytes induction in response to IL-6 and a induction as cells in response to IL-1, However, C/EBPα cells to IL-1 and IL-6 with the of induction as with IL-1 indicating that the gene was not in response to both cytokines. This our that the IL-6 pathway is not in C/EBPα hepatocytes. other gp130 signaling cytokines to rescue the induction of we hepatocytes with Oncostatin or or with and C/EBPα hepatocytes induction in response to the gp130 signaling cytokines However, both Oncostatin and in with IL-1 in both C/EBPα and hepatocytes with IL-1 both and hepatocytes to levels by hepatocytes with IL-1 and IL-6 whereas Oncostatin in with IL-1 to an or with hepatocytes to Oncostatin and IL-1 which a in the these demonstrate that the of the defect in the IL-6 pathway is to the IL-6Rα because other gp130 signaling activate STAT3 DNA binding and induce in C/EBPα hepatocytes. The acute phase response is a highly regulated response by the liver to inflammatory stimuli. laboratory previously reported that C/EBPα null mice unable to an APR in response to bacterial LPS (8Burgess-Beusse B.L. Darlington G.J. Mol. Cell. Biol. 1998; 18: 7269-7277Crossref PubMed Scopus (65) Google Scholar). This the mechanism of the defect in C/EBPα knock-out mice with hepatocytes in during the We demonstrate that C/EBPα is required in hepatocytes for proper of acute phase protein gene expression in response to inflammatory stimuli such as LPS or recombinant IL-1 and IL-6 cytokines. hepatocytes C/EBPα null are unable to activate the signaling pathway. We have shown that the lack of IL-6 signaling is to decreased protein levels of The decreased IL-6Rα protein levels are to decreased protein in C/EBPα null hepatocytes. However, gp130 and the other components of the IL-6 pathway are in C/EBPα null hepatocytes as demonstrated by the rescue of STAT3 activation and gene induction by with other gp130 signaling such as recombinant or Oncostatin in with The show the of IL-6-STAT3 signaling in the acute phase response in newborn IL-6Rα knock-out mice have not for However, of the acute phase response in IL-6 knock-out mice have shown that STAT3 and APP genes are in response to the systemic inflammatory LPS (10Fattori E. Cappelletti M. Costa P. Sellitto C. Cantoni L. Carelli M. Faggioni R. Fantuzzi P. J. 1994; PubMed Scopus Google Scholar). However, the have that other gp130 signaling cytokines be for this response in the IL-6 null The IL-6 knock-out mice and our C/EBPα knock-out mice with IL-6Rα levels in response to LPS be of the in the of mice as used in this not be to induce these gp130 signaling cytokines in response to LPS as gp130 to be in However, the of gp130 signaling in the acute phase response is by the lack of APP gene induction in gp130 knock-out mice M. T. T. J. 1998; PubMed Scopus Google Scholar). A of cytokine induction newborn and mice in the of this it is that C/EBPα null mice have other in to IL-6Rα levels that to In C/EBPα knock-out STAT3 was not in response to however, we to induce STAT3 DNA binding and APP gene expression in response to Oncostatin and that rescue of STAT3 activation with APP gene induction is in with previously (10Fattori E. Cappelletti M. Costa P. Sellitto C. Cantoni L. Carelli M. Faggioni R. Fantuzzi P. J. 1994; PubMed Scopus Google Scholar, T. E. Cappelletti M. 1998; PubMed Scopus Google Scholar, T. D. C. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). was in IL-6 mice that STAT3 was and APP genes with LPS as the whereas in response to turpentine the IL-6 mice not activate STAT3 and unable to induce APP gene expression (10Fattori E. Cappelletti M. Costa P. Sellitto C. Cantoni L. Carelli M. Faggioni R. Fantuzzi P. J. 1994; PubMed Scopus Google Scholar, T. E. Cappelletti M. 1998; PubMed Scopus Google Scholar). induces a localized inflammatory response, whereas LPS induces a systemic response, which a pathway and elevate other gp130 signaling cytokines such as Oncostatin or of STAT3 in liver has shown STAT3 to be a transcription factor required for APP gene induction in response to LPS T. D. C. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). IL-6Rα is required for IL-6 cytokine binding factor to for the gp130 signaling of the receptor C/EBPα has shown to be in and C/EBPα mice do not P. Darlington G.J. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). P. A. Darlington G.J. J. Scopus Google have shown that and protein levels of the IL-6Rα are highly reduced in liver and cells C/EBPα show that in to the previously of IL-6Rα levels in cells C/EBPα C/EBPα hepatocytes also have decreased IL-6Rα However, the mechanism of IL-6Rα regulation by C/EBPα to be cells at the and hepatocytes at the protein level. We have levels of IL-6Rα protein in C/EBPα null hepatocytes with hepatocytes. and the of IL-6Rα protein in hepatocytes to be as as in the hepatocytes. have shown the protein of IL-6Rα to be in of to our C. E. T. S. L. Eur. J. Biochem. 1994; PubMed Scopus Google Scholar). levels are by a variety of factors including levels, the of the of and the at which IL-6Rα In our we in levels of IL-6Rα in protein We in levels and protein as the of the in IL-6Rα protein In we the of IL-6Rα protein to be and C/EBPα to the in IL-6Rα protein the levels of IL-6Rα in C/EBPα hepatocytes in IL-6-STAT3 This that the IL-6Rα levels are a required for The that C/EBPα is a transcription factor localized to the that C/EBPα does not regulate the of IL-6Rα protein at the The regulation of IL-6Rα protein by C/EBPα in liver is by the that other such as and have levels of is that C/EBPα a gene protein the of IL-6Rα in hepatocytes. of IL-6Rα by and has in response to IL-6 however, is known the regulation of IL-6Rα IL-6 IL-6Rα is resulting in of IL-6 binding sites the by J.E. Fuller G.M. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar, D. L. S. H. E. 1992; PubMed Scopus Google Scholar). The of has shown to be by gp130 through a in the of gp130 E. S. C. J. T. L. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). a of IL-6Rα be by by a or by J. H. T. M. L. A. S. Eur. J. Immunol. 1993; PubMed Scopus Google Scholar, S. H. M. A. M. Eur. J. Immunol. 1994; PubMed Scopus Google Scholar). However, of IL-6Rα does not IL-6 signaling but the of IL-6 and cells gp130 that not be responsive to IL-6 M. S. Immunol. PubMed Scopus Google Scholar). is not in C/EBPα hepatocytes IL-6Rα is the or in the by an is that IL-6Rα is in C/EBPα hepatocytes because the hepatocytes respond to IL-6 Further of IL-6Rα protein regulation in C/EBPα hepatocytes of IL-6Rα protein In this we have shown that reduced IL-6Rα levels are for the lack of IL-6 signaling in C/EBPα hepatocytes by signaling with other gp130 signaling cytokines. is a recombinant to of the of the IL-6 which does not a to signal in the IL-6 receptor linked to IL-6 T. M. S. M. S. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to signal through gp130 to activate STAT3 T. M. S. M. S. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google whereas the cytokine, Oncostatin a high and gp130 signaling protein C. D. D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). have shown that Oncostatin and are of APP gene induction to IL-6 T. M. S. M. S. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Fantuzzi S. M. P. Cappelletti M. D. P. PubMed Google Scholar). We show that Oncostatin and activate STAT3 DNA binding and induce in C/EBPα hepatocytes with The has not however, T. D. C. Mol. Cell. Biol. 2001; PubMed Scopus Google conserved binding sites by which with the activation of in the of STAT3 in the We also that Oncostatin is a of STAT3 and IL-6 or This be to gp130 levels because gp130 signaling protein with gp130 proteins for IL-6R signaling T. T. Immunol. 1997; 15: PubMed Scopus Google Scholar). In this we show that the IL-6Rα is the of the IL-6 pathway in C/EBPα null hepatocytes by Oncostatin and to activate STAT3 DNA binding and induce C/EBPα is a transcription factor highly in hepatocytes. C/EBPα has shown to play roles in and in the liver A. Darlington G.J. 1995; PubMed Scopus Google Scholar, M. B.L. Darlington G.J. Mol. Cell. Biol. 1997; PubMed Google Scholar). In this we have shown that C/EBPα is required for IL-6 signaling in newborn hepatocytes. have to have and to the of C/EBPα knock-out mice Full Text PDF PubMed Google Scholar). it has that C/EBPα null mice as a for liver and the inflammatory of We for with the mice and for in hepatocyte and