The Nuclear Factor-κB Engages CBP/p300 and Histone Acetyltransferase Activity for Transcriptional Activation of the Interleukin-6 Gene Promoter

Abstract

Expression of the pleiotropic cytokine interleukin (IL)-6 can be stimulated by the proinflammatory cytokine tumor necrosis factor (TNF) and the microbial alkaloid staurosporine (STS). In this report, the transcriptional mechanisms were thoroughly investigated. Whereas transcription factors binding to the activator protein-1-, cAMP-responsive element-, and CAAT enhancer-binding protein-responsive sequences are necessary for gene activation by STS, nuclear factor (NF)-κB alone is responsible and sufficient for inducibility by TNF, which reveals distinct signaling pathways for both compounds. At the cofactor level, cAMP-responsive element-binding protein-binding protein (CBP) or p300 potentiate basal and induced IL-6 promoter activation via multiple protein-protein interactions with all transcription factors bound to the promoter DNA. However, the strongest promoter activation relies on the p65 NF-κB subunit, which specifically engages CBP/p300 for maximal transcriptional stimulation by its histone acetyltransferase activity. Moreover, treatment of chromatin-integrated promoter constructions with the histone deacetylase inhibitor trichostatin A exclusively potentiates TNF-dependent (i.e. NF-κB-mediated) gene activation, while basal or STS-stimulated IL-6 promoter activity remains completely unchanged. Similar observations were recorded with other natural NF-κB-driven promoters, namely IL-8 and endothelial leukocyte adhesion molecule (ELAM). We conclude that, within an “enhanceosome-like” structure, NF-κB is the central mediator of TNF-induced IL-6 gene expression, involving CBP/p300 and requiring histone acetyltransferase activity. Expression of the pleiotropic cytokine interleukin (IL)-6 can be stimulated by the proinflammatory cytokine tumor necrosis factor (TNF) and the microbial alkaloid staurosporine (STS). In this report, the transcriptional mechanisms were thoroughly investigated. Whereas transcription factors binding to the activator protein-1-, cAMP-responsive element-, and CAAT enhancer-binding protein-responsive sequences are necessary for gene activation by STS, nuclear factor (NF)-κB alone is responsible and sufficient for inducibility by TNF, which reveals distinct signaling pathways for both compounds. At the cofactor level, cAMP-responsive element-binding protein-binding protein (CBP) or p300 potentiate basal and induced IL-6 promoter activation via multiple protein-protein interactions with all transcription factors bound to the promoter DNA. However, the strongest promoter activation relies on the p65 NF-κB subunit, which specifically engages CBP/p300 for maximal transcriptional stimulation by its histone acetyltransferase activity. Moreover, treatment of chromatin-integrated promoter constructions with the histone deacetylase inhibitor trichostatin A exclusively potentiates TNF-dependent (i.e. NF-κB-mediated) gene activation, while basal or STS-stimulated IL-6 promoter activity remains completely unchanged. Similar observations were recorded with other natural NF-κB-driven promoters, namely IL-8 and endothelial leukocyte adhesion molecule (ELAM). We conclude that, within an “enhanceosome-like” structure, NF-κB is the central mediator of TNF-induced IL-6 gene expression, involving CBP/p300 and requiring histone acetyltransferase activity. Interleukin (IL) 1The abbreviations used are:ILinterleukinAPactivator proteinCBPcyclic AMP-responsive element-binding protein-binding proteinC/EBPCAAT enhancer-binding proteinCREBcyclic AMP-responsive element-binding proteinHAThistone acetyltransferaseHDAChistone deacetylaseRBPrecombination signal sequence-binding proteinSRCsteroid receptor coactivatorSTSstaurosporineTNFtumor necrosis factorTSAtrichostatin Awtwild-typeBSAbovine serum albuminbpbase pair(s)EMSAelectrophoretic mobility shift assayPBSphosphate-buffered salineNFnuclear factor-6 contributes to a multitude of physiological and pathophysiological processes. Among its many functions, IL-6 plays an active role in immunological responses, bone metabolism, reproduction, inflammation, neoplasia, and aging. Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis, Alzheimer's disease, and postmenopausal osteoporosis. The cellular and molecular biology of IL-6 has been explored by a variety of approaches (1Gadient R.A. Otten U.H. Prog. Neurobiol. 1997; 52: 379-390Crossref PubMed Scopus (431) Google Scholar). In view of its pleiotropic functions, studies on the regulation of IL-6 gene expression may be of prior importance. The characterization of the IL-6 promoter revealed a complex control region that can be triggered by multiple activation pathways (2Dendorfer U. Oettgen P. Libermann T.A. Mol. Cell. Biol. 1994; 14: 4443-4454Crossref PubMed Scopus (299) Google Scholar, 3Vanden Berghe W. Plaisance S. Boone E. De Bosscher K. Schmitz M.L. Fiers W. Haegeman G. J. Biol. Chem. 1998; 273: 3285-3290Abstract Full Text Full Text PDF PubMed Scopus (621) Google Scholar). In the case of tumor necrosis factor (TNF), the main transcriptional activator for IL-6 gene induction is the nuclear factor NF-κB, which is typically a dimer between p50 and the transactivating subunit p65 (RelA). In unstimulated cells, NF-κB resides in the cytoplasm, bound to its inhibitor IκB. After cell stimulation, NF-κB is released from IκB and migrates into the nucleus, where it induces gene expression after DNA binding (4May M.J. Ghosh S. Immunol. Today. 1998; 19: 80-88Abstract Full Text Full Text PDF PubMed Scopus (1052) Google Scholar). Access of NF-κB complexes is partially blocked by the constitutive occupancy of the IL-6-κB site by the recombination signal sequence-binding protein (RBP)-Jκ, which is involved in the constitutive repression of the IL-6 gene under normal physiological conditions (5Plaisance S. Vanden Berghe W. Boone E. Fiers W. Haegeman G. Mol. Cell. Biol. 1997; 17: 3733-3743Crossref PubMed Google Scholar). Activation of IL-6 gene expression by NF-κB is probably the most important pathway. For maximum response, additional factors are also required, the most important being activator protein (AP)-1, cyclic AMP-responsive element-binding protein (CREB) and CAAT enhancer-binding protein (C/EBP) (6Keller E.T. Wanagat J. Ershler W.B. Frontiers Biosci. 1996; 1: d340-d357Crossref PubMed Scopus (128) Google Scholar, 7Koj A. Biochim. Biophys. Acta. 1996; 1317: 84-94Crossref PubMed Scopus (279) Google Scholar). AP-1 is formed by the dimerization of Fos and Jun family members through a leucine zipper structural motif and becomes activated by mitogenic stimuli, oncoproteins, cytokines, and UV light. Another dimeric transcription factor is CREB, which binds to cAMP-responsive elements and is involved in cAMP-signaling pathways. The C/EBP family of transcription factors is involved in the expression of both acute phase cytokine genes and cytokine-inducible acute-phase proteins. interleukin activator protein cyclic AMP-responsive element-binding protein-binding protein CAAT enhancer-binding protein cyclic AMP-responsive element-binding protein histone acetyltransferase histone deacetylase recombination signal sequence-binding protein steroid receptor coactivator staurosporine tumor necrosis factor trichostatin A wild-type bovine serum albumin base pair(s) electrophoretic mobility shift assay phosphate-buffered saline nuclear factor Transcription is a multistep process with many potential levels of control. Recent data indicate that numerous transcription factors mediate their effects via recruitment of cofactors (8Korzus E. Torchia J. Rose D.W. Xu L. Kurokawa R. McInerney E.M. Mullen T.M. Glass C.K. Rosenfeld M.G. Science. 1998; 279: 703-707Crossref PubMed Scopus (560) Google Scholar, 9Merika M. Williams A.J. 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Boone E. De D. K. Haegeman G. Fiers W. Google Scholar). In the the transcriptional mechanisms of and IL-6 gene We on the between or factors and the cofactor CBP/p300 in the IL-6 promoter The between activity and IL-6 promoter stimulation explored with a p300 and with the inhibitor trichostatin A also observations to other and were in with and were in such that were the of the has been Berghe W. Plaisance S. Boone E. De Bosscher K. Schmitz M.L. Fiers W. Haegeman G. J. Biol. Chem. 1998; 273: 3285-3290Abstract Full Text Full Text PDF PubMed Scopus (621) Google Scholar). from and as a in from and as a in that the of used with of the IL-6 levels were in a assay U. J. Immunol. PubMed Scopus Google Scholar). The IL-6 and were Berghe W. Plaisance S. Boone E. De Bosscher K. Schmitz M.L. Fiers W. Haegeman G. J. Biol. Chem. 1998; 273: 3285-3290Abstract Full Text Full Text PDF PubMed Scopus (621) Google S. Vanden Berghe W. Boone E. Fiers W. Haegeman G. Mol. Cell. 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Vanden Berghe W. Boone E. Fiers W. Haegeman G. Mol. Cell. Biol. 1997; 17: 3733-3743Crossref PubMed Google Scholar). The binding sequences for the and For were with a of For and were to the addition of the The conditions were as (10Gerritsen M.E. Williams A.J. Neish A.S. Moore S. Shi Y. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2927-2932Crossref PubMed Scopus (717) Google Scholar). were in on after of the expression of protein from cell with or an as control in a of After of protein with and on a for were to with after with to the were on for in were stimulated for after which were with and for in were in and for in with to in were in for after which were with in for After with in for were for after which were under a were recorded a to a were by Cell were for and gene as Berghe W. Plaisance S. Boone E. De Bosscher K. Schmitz M.L. Fiers W. Haegeman G. J. Biol. 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J. 1996; PubMed Scopus Google on gene After of IL-6 promoter in cells, the were for their to and After of the IL-6 promoter from the a inducibility by is in the promoter the AP-1 as with the the inducibility by is completely in the and IL-6 promoter in which the upstream elements for AP-1, and C/EBP are The inducibility by TNF, remains for the for in which the NF-κB motif is activation mechanisms after stimulation of the IL-6 promoter by or In to the of IL-6 promoter were also for their to or as treatment is the the NF-κB motif inducibility the all on activation by that elements other the NF-κB motif are involved in the to STS, of the AP-1, CREB, or C/EBP elements partially the inducibility by and a in the activation with the observations with and and in a of both in the AP-1, C/EBP, or NF-κB motif all the of for the role of NF-κB in inducibility and of AP-1 or in to from gene sequences for AP-1, CREB, or NF-κB in of an Whereas the NF-κB exclusively to and to STS, the and AP-1 to to of p300, and with IL-6 factors has been the of the p50 and p65 NF-κB with p300, or in of signaling with the expression levels of by or W. B. W. 1998; PubMed Scopus Google were in the of or a of transcription factor interactions with can be in the of stimuli, by constitutive D. A.S. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). basal IL-6 promoter activity is induced after of of p50 the promoter activity. is in with the and of in the p65 and p50 a promoter activation of after of p65 with p300 or a activation with the other basal IL-6 promoter activity with with may be that IL-6 promoter stimulation with p300 or in the of also gene activity AP-1, CREB, and C/EBP are bound to their elements and have been to also with of the AP-1 subunit addition to the of under conditions to used for p65 basal or IL-6 promoter activity. a and role for p65 in coactivator effects with CBP/p300 within the IL-6 promoter and to their activity in transcriptional the between p65 and with were to with by with p65 is to from the cell which a and distinct between were and with to of p65 protein We the of interactions with AP-1, C/EBP, CREB, or NF-κB in basal or IL-6 gene of the or elements a on basal promoter while in the C/EBP or NF-κB elements are a of effects is in the or The role of interactions in the activated of the IL-6 promoter also NF-κB activation by of p65 the IL-6 promoter of the NF-κB motif the induction of the other of p65 and in a of IL-6 promoter activity with the promoter and the promoter this the case for the NF-κB where the is and where the induction is to the promoter activity in the of promoter activation after of and p65 also effects with the bound factors, the in the AP-1, C/EBP the of promoter the between p65 and (i.e. the activity of and p65 remains data that is in the IL-6 promoter complex by multiple protein-protein interactions with transcription factors bound or activated by transcriptional and including have been to be an important role of CBP/p300 in IL-6 promoter the of CBP/p300 its factors to be an of the activation for promoter We the of CBP/p300 function in IL-6 promoter activation after of p65 with p300 or the between p65 and p300 is after of the this is by a of activity J. 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Biol. 1997; 17: 3733-3743Crossref PubMed Google the which an role of Similar can be from multiple of or elements in of a in this a is with the NF-κB gene while the STS-stimulated gene activity remains the constitutive which is completely to data an between the in IL-6 promoter activation and potentiates gene cell of IL-6 promoter and gene with elements were or were with for with for with or in the of were for gene expression and for protein of in were or with for levels were revealed with effects are as by the of induction factor of a treatment with or NF-κB to play a role in on IL-6 gene expression, by of and other promoters, such as the IL-8 and promoters, to a treatment with TNF, STS, or to of cell of IL-8 and promoter gene were with or alone or with their and the were for gene expression expression levels were in to in both which is in with the of or NF-κB in the IL-8 and N. Y. K. J. Biol. Chem. Full Text PDF PubMed Google Scholar, T. Neish A.S. Thanos D. T. J. 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In the explored the IL-6 promoter may be by or and the for promoter stimulation be the transcription factor and cofactor We that and IL-6 gene transcription can be Whereas NF-κB alone is responsible and sufficient for to TNF, binding factors such as AP-1, CREB, or C/EBP are for gene into the cofactor regulation in IL-6 promoter stimulation revealed a between p65 and which is on its conditions of treatment with TNF-dependent (i.e. NF-κB-mediated) gene activation is while basal or STS-stimulated IL-6 promoter activity remains completely unchanged. The between the of and activated NF-κB by the that the NF-κB completely the may that the IL-6 promoter is the NF-κB site by an of a coactivator complex including with NF-κB, and a complex with In the of activated NF-κB, the IL-6-κB site is by (5Plaisance S. Vanden Berghe W. Boone E. Fiers W. Haegeman G. Mol. Cell. 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