Glucocorticoid Ligands Specify Different Interactions with NF-κB by Allosteric Effects on the Glucocorticoid Receptor DNA Binding Domain

Glucocorticoids inhibit inflammation by acting through the glucocorticoid receptor (GR) and powerfully repressing NF-κB function. Ligand binding to the C-terminal of GR promotes the nuclear translocation of the receptor and binding to NF-κB through the GR DNA binding domain. We sought how ligand recognition influences the interaction between NF-κB and GR. Both dexamethasone (agonist) and RU486 (antagonist) promote efficient nuclear translocation, and we show occupancy of the same intranuclear compartment as NF-κB with both ligands. However, unlike dexamethasone, RU486 had negligible activity to inhibit NF-κB transactivation. This failure may stem from altered co-factor recruitment or altered interaction with NF-κB. Using both glutathione S-transferase pull-down and bioluminescence resonance energy transfer approaches, we identified a major glucocorticoid ligand effect on interaction between the GR and the p65 component of NF-κB, with RU486 inhibiting recruitment compared with dexamethasone. Using the bioluminescence resonance energy transfer assay, we found that RU486 efficiently recruited NCoR to the GR, unlike dexamethasone, which recruited SRC1. Therefore, RU486 promotes differential protein recruitment to both the C-terminal and DNA binding domain of the receptor. Importantly, using chromatin immunoprecipitation, we show that impaired interaction between GR and p65 with RU486 leads to reduced recruitment of the GR to the NF-κB-responsive region of the interleukin-8 promoter, again in contrast to dexamethasone that significantly increased GR binding. We demonstrate that ligand-induced conformation of the GR C-terminal has profound effects on the functional surface generated by the DNA binding domain of the GR. This has implications for understanding ligand-dependent interdomain communication. Glucocorticoids inhibit inflammation by acting through the glucocorticoid receptor (GR) and powerfully repressing NF-κB function. Ligand binding to the C-terminal of GR promotes the nuclear translocation of the receptor and binding to NF-κB through the GR DNA binding domain. We sought how ligand recognition influences the interaction between NF-κB and GR. Both dexamethasone (agonist) and RU486 (antagonist) promote efficient nuclear translocation, and we show occupancy of the same intranuclear compartment as NF-κB with both ligands. However, unlike dexamethasone, RU486 had negligible activity to inhibit NF-κB transactivation. This failure may stem from altered co-factor recruitment or altered interaction with NF-κB. Using both glutathione S-transferase pull-down and bioluminescence resonance energy transfer approaches, we identified a major glucocorticoid ligand effect on interaction between the GR and the p65 component of NF-κB, with RU486 inhibiting recruitment compared with dexamethasone. Using the bioluminescence resonance energy transfer assay, we found that RU486 efficiently recruited NCoR to the GR, unlike dexamethasone, which recruited SRC1. Therefore, RU486 promotes differential protein recruitment to both the C-terminal and DNA binding domain of the receptor. Importantly, using chromatin immunoprecipitation, we show that impaired interaction between GR and p65 with RU486 leads to reduced recruitment of the GR to the NF-κB-responsive region of the interleukin-8 promoter, again in contrast to dexamethasone that significantly increased GR binding. We demonstrate that ligand-induced conformation of the GR C-terminal has profound effects on the functional surface generated by the DNA binding domain of the GR. This has implications for understanding ligand-dependent interdomain communication. Glucocorticoids (GCs) 1The abbreviations used are: GC, glucocorticoid; GR, glucocorticoid receptor; NRE, NF-κB response element; RHD, Rel homology domain; GST, glutathione S-transferase; Dex, dexamethasone; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; TNF, transforming growth factor; IL, interleukin; ELISA, enzyme-linked immunosorbent assay; BRET, bioluminescence resonance energy transfer; YFP, yellow fluorescence protein; EYFP, enhanced YFP; RID, receptor-interacting domain; DBD, DNA binding domain; LBD, ligand-binding domain.1The abbreviations used are: GC, glucocorticoid; GR, glucocorticoid receptor; NRE, NF-κB response element; RHD, Rel homology domain; GST, glutathione S-transferase; Dex, dexamethasone; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; TNF, transforming growth factor; IL, interleukin; ELISA, enzyme-linked immunosorbent assay; BRET, bioluminescence resonance energy transfer; YFP, yellow fluorescence protein; EYFP, enhanced YFP; RID, receptor-interacting domain; DBD, DNA binding domain; LBD, ligand-binding domain. activate the cytosolic glucocorticoid receptor (GR), which translocates to the nucleus to regulate gene expression. The anti-inflammatory activities of GCs are caused, in part, by transrepression of the proinflammatory transcription factor NF-κB. The GR has distinct functional domains, an N-terminal transactivation domain (AF-1), a central DNA binding domain (DBD), and a C-terminal domain that includes ligand binding (LBD) and transactivation activities (AF-2) (1Hollenberg S.M. Weinberger C. Ong E.S. Cerelli G. Oro A. Lebo R. Thompson E.B. Rosenfeld M.G. Evans R.M. Nature. 1985; 318: 635-641Crossref PubMed Scopus (1430) Google Scholar, 2Giguere V. Hollenberg S.M. Rosenfeld M.G. Evans R.M. Cell. 1986; 46: 645-652Abstract Full Text PDF PubMed Scopus (672) Google Scholar, 3Iniguez-Lluhi J.A. Lou D.Y. Yamamoto K.R. J. Biol. Chem. 1997; 272: 4149-4156Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). However, although the domains can function separately, there is evidence for functional interdependence within the intact GR, which may be necessary for authentic activity (4Hittelman A.B. Burakov D. Iniguez-Lluhi J.A. Freedman L.P. Garabedian M.J. EMBO J. 1999; 18: 5380-5388Crossref PubMed Scopus (239) Google Scholar). For example, the conformation of the DBD, induced by either DNA sequence or protein binding, can determine whether transcription is induced or repressed (5Lefstin J.A. Yamamoto K.R. Nature. 1998; 392: 885-888Crossref PubMed Scopus (436) Google Scholar). The chemical structure of glucocorticoid ligands alter the function of the receptor as they induce conformational changes to the LBD that specify whether co-activators or co-repressors are recruited (6Bledsoe R.K. Montana V.G. Stanley T.B. Delves C.J. Apolito C.J. McKee D.D. Consler T.G. Parks D.J. Stewart E.L. Willson T.M. Lambert M.H. Moore J.T. Pearce K.H. Xu H.E. Cell. 2002; 110: 93-105Abstract Full Text Full Text PDF PubMed Scopus (660) Google Scholar, 7Kauppi B. Jakob C. Farnegardh M. Yang J. Ahola H. Alarcon M. Calles K. Engstrom O. Harlan J. Muchmore S. Ramqvist A.K. Thorell S. Ohman L. Greer J. Gustafsson J.A. Carlstedt-Duke J. Carlquist M. J. Biol. Chem. 2003; 278: 22748-22754Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). For example, both the GR agonist dexamethasone and the antagonist RU486 promote nuclear translocation and DNA-binding of the GR (8Qi M. Stasenko L.J. DeFranco D.B. Mol. Endocrinol. 1990; 4: 455-464Crossref PubMed Scopus (41) Google Scholar, 9Htun H. Barsony J. Renyi I. Gould D.L. Hager G.L. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4845-4850Crossref PubMed Scopus (323) Google Scholar, 10Schmidt T.J. J. Steroid Biochem. 1986; 24: 853-863Crossref PubMed Scopus (32) Google Scholar, 11Beck C.A. Estes P.A. Bona B.J. Muro-Cacho C.A. Nordeen S.K. Edwards D.P. Endocrinology. 1993; 133: 728-740Crossref PubMed Scopus (61) Google Scholar); however, when RU486 is bound, the position of helix 12, as shown by the recent crystal structure, is altered and partially blocks the co-activator pocket (7Kauppi B. Jakob C. Farnegardh M. Yang J. Ahola H. Alarcon M. Calles K. Engstrom O. Harlan J. Muchmore S. Ramqvist A.K. Thorell S. Ohman L. Greer J. Gustafsson J.A. Carlstedt-Duke J. Carlquist M. J. Biol. Chem. 2003; 278: 22748-22754Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). This leads to the recruitment of co-repressors, such as NCoR, and not co-activators, such as SRC1, which are recruited to the agonist bound GR (12Stevens A. Garside H. Berry A. Waters C. White A. Ray D. Mol. Endocrinol. 2003; 17: 845-859Crossref PubMed Scopus (47) Google Scholar, 13Schulz M. Eggert M. Baniahmad A. Dostert A. Heinzel T. Renkawitz R. J. Biol. Chem. 2002; 277: 26238-26243Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). However, the effects of these ligand-induced conformational changes on the function of the DNA binding domain have not been fully explored. The mechanism of NF-κB repression by GR has yet to be fully defined, but it is known that GR and the p65 subunit of NF-κB physically interact (14Caldenhoven E. Liden J. Wissink S. Van de S.A. Raaijmakers J. Koenderman L. Okret S. Gustafsson J.A. Van der Saag P.T. Mol. Endocrinol. 1995; 9: 401-412Crossref PubMed Google Scholar, 15Ray A. Prefontaine K.E. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 752-756Crossref PubMed Scopus (913) Google Scholar, 16Scheinman R.I. Gualberto A. Jewell C.M. Cidlowski J.A. Baldwin Jr., A.S. Mol. Cell. Biol. 1995; 15: 943-953Crossref PubMed Google Scholar, 17McKay L.I. Cidlowski J.A. Mol. Endocrinol. 1998; 12: 45-56Crossref PubMed Scopus (304) Google Scholar) with the GR DBD binding to the Rel homology domain (RHD) of p65 (18Nissen R.M. Yamamoto K.R. Genes Dev. 2000; 14: 2314-2329Crossref PubMed Scopus (454) Google Scholar). This interaction occurs on the NF-κB response element resulting in “tethering” of the GR to DNA. GR repression of p65 requires the LBD, in addition to the DBD (19McKay L.I. Cidlowski J.A. Endocr. Rev. 1999; 20: 435-459Crossref PubMed Google Scholar). A repressor protein or complex, recruited to the tethered GR, has been proposed, with evidence implicating GRIP-1, a member of the p160 family (18Nissen R.M. Yamamoto K.R. Genes Dev. 2000; 14: 2314-2329Crossref PubMed Scopus (454) Google Scholar, I. Yamamoto K.R. EMBO J. 20: PubMed Scopus Google Scholar, I. Yamamoto K.R. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google Scholar). However, it is not functional between agonist and antagonist are to interaction with NF-κB or recruitment of the The function of the GR DBD has been to be of the LBD, but RU486 of DNA binding for the GR compared with dexamethasone S. G. A. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). we the of ligand on functional between the ligand binding domain and DNA binding domain of the GR. understanding of how GR interaction with p65 occurs and how can be by ligand has major implications for and we a for the GR LBD in recruitment of NF-κB to the GR DNA binding domain. of of the NF-κB response of the it to p65 and has been D. Rosenfeld M.G. T. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The p65 using the and the protein to The had and for the for p65 from the using and The by White and has been G. L. E. E. White J. Sci. 2002; PubMed Google Scholar). and using the and or The had and for the for for The and by For the of the GR sequence from and to a the from using and and For the of the GR sequence from and to a GR the from using and and to the p65 sequence of either the or using the of and for p65 and for p65 For the the the used and and the the the protein by using and and the The GR has been (12Stevens A. Garside H. Berry A. Waters C. White A. Ray D. Mol. Endocrinol. 2003; 17: 845-859Crossref PubMed Scopus (47) Google Scholar). The GR DNA binding binding domain between and from using the and the to The had and for the for The from and has been (12Stevens A. Garside H. Berry A. Waters C. White A. Ray D. Mol. Endocrinol. 2003; 17: 845-859Crossref PubMed Scopus (47) Google Scholar). to the of the changes and to of of and the in S-transferase and in and as C. Gustafsson J.A. Biochem. J. 2003; PubMed Scopus Google Scholar). a of the with and for The and in with The with for and using a on for The to the and to the The to to the for The in and GR using the the with the GR in or as with Dex, or RU486 and GR with the bound to for The in and in the bound by and the in to the The GR by of the to a The 2000; The of protein on the using a and and with of and of GR or and of to both and for as (12Stevens A. Garside H. Berry A. Waters C. White A. Ray D. Mol. Endocrinol. 2003; 17: 845-859Crossref PubMed Scopus (47) Google Scholar). DMEM, and the of the by growth with and using to the with GR to the or and p65 to the or using and a for with using and for in Dulbecco's with and and in to a of to of a by in that the dexamethasone and The for for the by of the to a of on a using the for and for enhanced yellow protein of the with from the of the as the between and DMEM, and using the The on the with of reduced The a using of reduced of and of on the with C-terminal and the protein to SRC1, or a of and by DMEM, and in and in as for the with GR ligands in that the between and The in the of for for the by of the to a of and on a using the for and for The for the from with the protein as and using a in with for from with and a response of either or RU486 for using an the of of using with and the with and either or RU486 for with and for with with and with for A of for the GR, for p65 from in for with and a of the or in for The and on using and using a using a using an and using a of and a of using an of and using a of in with and a of with of either or using on a using a with an and using a of for in with to in with or and GR ligand for and with and for for to the The by J. M. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) with PBS, for and for with of PBS, and in of and for the by for and to in and to The to the and DNA using the The with of of and of protein for using either of GR or of p65 immunoprecipitation, of protein and of DNA and the for for in and with and with and to the DNA using the DNA using the for of the and which have been (18Nissen R.M. Yamamoto K.R. Genes Dev. 2000; 14: 2314-2329Crossref PubMed Scopus (454) Google Scholar) region and region and and of DNA of DNA in by with from with of DNA. for the of DNA from the and the of DNA in the the of the and to that with both a and by using of by the but RU486 the of GR ligands to for with in the or of in by increased significantly by RU486 not significantly of GR and NF-κB p65 in and RU486 GR translocation, and both promote DNA binding S. G. A. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google but RU486 to we to the effect of these ligands on the nuclear of GR and GR found in the nucleus when with either or with a and The intranuclear of p65 compared with GR, but there and in a and Therefore, the failure of RU486 to NF-κB the GR a intranuclear with both ligands. of between p65 and GR DBD and the Rel homology domain of p65 interact the effects of ligand on a pull-down The Rel homology domain of p65 bound GR in the of ligand This interaction not significantly altered by Dex, it significantly by the same of ligand-dependent recruitment when the with the of the GR a and the GR in transrepression (18Nissen R.M. Yamamoto K.R. Genes Dev. 2000; 14: 2314-2329Crossref PubMed Scopus (454) Google Scholar). that the to NF-κB, we compared activity to GR in an gene response to dexamethasone, the of to p65 transactivation not significantly from GR ligand of in the in pull-down it that GR ligand interaction with However, in may Therefore, of the of ligand sought in using on energy transfer from to a protein with the of the fluorescence to is We with both on either the or the using a This that to the C-terminal of the GR the with a of protein to the C-terminal of p65 with and This of the of GR and p65 in The response when with an of to between GR and p65 of and a of and not the not A in the of with either C-terminal or C-terminal or N-terminal for of of the used in the of the used in the of the in in and with of and using a A and and of the the of the of the The of the with either or that of the protein the a nuclear with V. S. A. I. Evans R.M. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). Both the and the to the of nuclear in and the of the to be by for the not A of not a interaction between GR and p65 as in the pull-down The addition of either or RU486 a in with an of for and for RU486 a and using either not or both ligands the in induced by RU486 of the the of of NF-κB p65 by the we with The addition of to the had effect on the GR it is to of the p160 co-activator such as SRC1, to ligand binding the binding of the antagonist RU486 such interaction (12Stevens A. Garside H. Berry A. Waters C. White A. Ray D. Mol. Endocrinol. 2003; 17: 845-859Crossref PubMed Scopus (47) Google Scholar). We found that increased the in a with an of in RU486 to a The induced by by of RU486 not RU486 to to the GR, and recent has shown that such as NCoR are recruited (12Stevens A. Garside H. Berry A. Waters C. White A. Ray D. Mol. Endocrinol. 2003; 17: 845-859Crossref PubMed Scopus (47) Google Scholar, 13Schulz M. Eggert M. Baniahmad A. Dostert A. Heinzel T. Renkawitz R. J. Biol. Chem. 2002; 277: 26238-26243Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). We found that RU486 increased the in a with an of to the RU486 of GR to the that ligand recognition influences the functional surface on the GR for recruitment of NF-κB. However, on there may be an by the DNA Therefore, we sought interaction between the GR and NF-κB on a on the using chromatin a we used a region of the promoter, which is not by either NF-κB or GR (18Nissen R.M. Yamamoto K.R. Genes Dev. 2000; 14: 2314-2329Crossref PubMed Scopus (454) Google Scholar). Using an we a of NF-κB p65 binding to the element in response to of the with but changes with or However, using GR we in DNA when with and with both and dexamethasone, there a in the of DNA with and the in DNA compared with or significantly the with dexamethasone and of a region on the promoter, which is not by either GR or but had to the from the the with in using either we both in and in that glucocorticoid receptor ligands regulate recruitment of NF-κB p65 to the GR DNA binding domain. has been that ligands for the nuclear to functional the C-terminal and recruitment of However, we show that ligand-induced conformational changes to the DNA binding domain of the GR, to be in function. had of RU486 on gene we glucocorticoid repression by both and RU486 in We found that there negligible repression of when of RU486 repression of by Dex, an for effect of of GR induced by RU486 or not in nuclear translocation or DNA binding (8Qi M. Stasenko L.J. DeFranco D.B. Mol. Endocrinol. 1990; 4: 455-464Crossref PubMed Scopus (41) Google Scholar, 9Htun H. Barsony J. Renyi I. Gould D.L. Hager G.L. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4845-4850Crossref PubMed Scopus (323) Google Scholar, 10Schmidt T.J. J. Steroid Biochem. 1986; 24: 853-863Crossref PubMed Scopus (32) Google Scholar, 11Beck C.A. Estes P.A. Bona B.J. Muro-Cacho C.A. Nordeen S.K. Edwards D.P. Endocrinology. 1993; 133: 728-740Crossref PubMed Scopus (61) Google Scholar). H. Barsony J. Renyi I. Gould D.L. Hager G.L. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4845-4850Crossref PubMed Scopus (323) Google Scholar) in the intranuclear of GR induced by either RU486 or Dex, not either with protein or with in and not are between the used in and by H. Barsony J. Renyi I. Gould D.L. Hager G.L. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4845-4850Crossref PubMed Scopus (323) Google Scholar). in the a GR the an N-terminal and a The between the N-terminal and the GR the a with of The of the N-terminal and the may be For these we the intranuclear of the GR. We not in the intranuclear of the GR in the of dexamethasone compared with is that of the modified GR differential induced by the but in using and chromatin immunoprecipitation, we used GR, and we that is Therefore, the effects of and RU486 on NF-κB function are to be by in or intranuclear of GR from p65 have been to the mechanism of of for and of J.A. C. A. M. 1995; PubMed Scopus Google Scholar) R.I. Gualberto A. Jewell C.M. Cidlowski J.A. Baldwin Jr., A.S. Mol. Cell. Biol. 1995; 15: 943-953Crossref PubMed Google Scholar, Xu L. Heinzel T. J. R. B. Rosenfeld M.G. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D. Rosenfeld M.G. T. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, V. S. A. I. Evans R.M. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). has been shown that GR not NF-κB from binding on the promoter, but repressor in a mechanism (18Nissen R.M. Yamamoto K.R. Genes Dev. 2000; 14: 2314-2329Crossref PubMed Scopus (454) Google Scholar). by I. Yamamoto K.R. EMBO J. 20: PubMed Scopus Google Scholar) that the co-activator is to repression of NF-κB activity on the gene and found for in The failure of the GR to as a may failure to However, as RU486 recruitment of the repressor protein NCoR, it be to inhibit NF-κB in a to that of the which NF-κB by activity to the I. Yamamoto K.R. EMBO J. 20: PubMed Scopus Google Scholar, I. Yamamoto K.R. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google Scholar). the interaction of GR with we a pull-down The GR to interact with the of p65 in by Dex, interaction by and interaction between GR and p65 in the has been (18Nissen R.M. Yamamoto K.R. Genes Dev. 2000; 14: 2314-2329Crossref PubMed Scopus (454) Google Scholar). both the GR and p65 are in in the it that such an interaction be in the of However, recent by C. Gustafsson J.A. Biochem. J. 2003; PubMed Scopus Google Scholar) that there may be a interaction between the GR and the and The of interaction between GR and p65 with RU486 is and effects from the on the RU486 interaction between p65 and a GR that transrepression activity when it is bound to GR of a effect of ligand on GR protein recruitment in of a in the of in by protein of with and the with either for or a of protein for The with a C-terminal p65 and a C-terminal GR. This that the of both are in to using the assay, and the is for of The DNA binding domain of GR and the Rel homology domain of p65 have been identified as the as the of both are in it is that may between the or that of the is for functional The in the addition of both and RU486 an in binding between GR and p65 or a in conformation of the protein The addition of to the to significantly alter the in the This may be to the that on a Therefore, translocation of protein from these not significantly the Both and RU486 a in the with the the ligands for binding to the GR. the in for the antagonist RU486 compared with the agonist are of the conformational in the GR LBD induced by RU486 may the on GR from the on the of energy or RU486 may in significantly interaction with p65 with a conformational in the GR LBD that the on GR to the of This is with the reduced interaction in the pull-down but that a of GR is bound to NF-κB between in and in be to the of for interaction in in and by has that promotes the recruitment of but not NCoR to the GR LBD, RU486 promotes the recruitment of NCoR but not (12Stevens A. Garside H. Berry A. Waters C. White A. Ray D. Mol. Endocrinol. 2003; 17: 845-859Crossref PubMed Scopus (47) Google Scholar, 13Schulz M. Eggert M. Baniahmad A. Dostert A. Heinzel T. Renkawitz R. J. Biol. Chem. 2002; 277: 26238-26243Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). ligand-dependent protein recruitment to the GR, using the both and NCoR are and used to The NCoR the receptor-interacting domains by M. Eggert M. Baniahmad A. Dostert A. Heinzel T. Renkawitz R. J. Biol. Chem. 2002; 277: 26238-26243Abstract Full Text Full Text PDF PubMed Scopus (120) Google and we used a as (12Stevens A. Garside H. Berry A. Waters C. White A. Ray D. Mol. Endocrinol. 2003; 17: 845-859Crossref PubMed Scopus (47) Google Scholar, E. S. M.G. Nature. 1997; PubMed Scopus Google Scholar). by interaction between GR and in RU486 between GR and NCoR, as from (12Stevens A. Garside H. Berry A. Waters C. White A. Ray D. Mol. Endocrinol. 2003; 17: 845-859Crossref PubMed Scopus (47) Google Scholar, 13Schulz M. Eggert M. Baniahmad A. Dostert A. Heinzel T. Renkawitz R. J. Biol. Chem. 2002; 277: 26238-26243Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). Importantly, in of the as as the for GR in However, of altered interaction between the GR and NF-κB p65 either in or in not the effects of DNA binding on NF-κB Therefore, we to GR interaction with the NF-κB on the in of the of NF-κB p65 binding to the NF-κB to a as in (18Nissen R.M. Yamamoto K.R. Genes Dev. 2000; 14: 2314-2329Crossref PubMed Scopus (454) Google Scholar). found that GR ligand not the of p65 on the promoter, in with We found in GR occupancy of the in response to but a with and a in GR occupancy in response to which the repression of RU486 both interaction between the GR and NF-κB and recruitment of GR to NF-κB, mechanism to the failure of RU486 to inhibit show that ligand-induced of the GR regulate interaction between GR and NF-κB, in addition to recruitment of to the GR This effect and between the and DNA binding domain of the GR. in which the functional domains of the GR interact to regulate gene

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