Inhibition of AP-1 by the Glucocorticoid-inducible Protein GILZ

Abstract

The immunosuppressive effects of glucocorticoids arise largely by inhibition of cytokine gene expression, which has been ascribed to interference between the glucocorticoid receptor and transcription factors such as AP-1 and NF-κB as well as by competition for common coactivators. Here we show that glucocorticoid-induced inhibition of interleukin-2 mRNA expression in activated normal T cells required new protein synthesis, suggesting that this phenomenon is secondary to expression of glucocorticoid-regulated genes. One of the most prominent glucocorticoid-induced genes is glucocorticoid-induced leucine zipper (GILZ), which has been reported to inhibit activation-induced up-regulation of Fas ligand (FasL) mRNA. Indeed, transient expression of GILZ in Jurkat T cells blocked induction of a reporter construct driven by the FasL promoter. This could be accounted for by GILZ-mediated inhibition of Egr-2 and Egr-3, NFAT/AP-1-inducible transcription factors that bind a regulatory element in the FasL promoter and up-regulate FasL expression. GILZ also potently inhibited AP-1-driven and IL-2 promoter-driven reporter constructs, and recombinant GILZ specifically interacted with c-Fos and c-Jun in vitro and inhibited the binding of active AP-1 to its target DNA. Whereas homodimerization of GILZ required the presence of its leucine zipper, the interaction with c-Fos and c-Jun occurred through the N-terminal 60-amino acid region of GILZ. Thus, GILZ represents a glucocorticoid-induced gene product that can inhibit a variety of activation-induced events, at least in part by direct interference with AP-1, and is therefore a candidate for a mediator of glucocorticoid-induced immunosuppression. The immunosuppressive effects of glucocorticoids arise largely by inhibition of cytokine gene expression, which has been ascribed to interference between the glucocorticoid receptor and transcription factors such as AP-1 and NF-κB as well as by competition for common coactivators. Here we show that glucocorticoid-induced inhibition of interleukin-2 mRNA expression in activated normal T cells required new protein synthesis, suggesting that this phenomenon is secondary to expression of glucocorticoid-regulated genes. One of the most prominent glucocorticoid-induced genes is glucocorticoid-induced leucine zipper (GILZ), which has been reported to inhibit activation-induced up-regulation of Fas ligand (FasL) mRNA. Indeed, transient expression of GILZ in Jurkat T cells blocked induction of a reporter construct driven by the FasL promoter. This could be accounted for by GILZ-mediated inhibition of Egr-2 and Egr-3, NFAT/AP-1-inducible transcription factors that bind a regulatory element in the FasL promoter and up-regulate FasL expression. GILZ also potently inhibited AP-1-driven and IL-2 promoter-driven reporter constructs, and recombinant GILZ specifically interacted with c-Fos and c-Jun in vitro and inhibited the binding of active AP-1 to its target DNA. Whereas homodimerization of GILZ required the presence of its leucine zipper, the interaction with c-Fos and c-Jun occurred through the N-terminal 60-amino acid region of GILZ. Thus, GILZ represents a glucocorticoid-induced gene product that can inhibit a variety of activation-induced events, at least in part by direct interference with AP-1, and is therefore a candidate for a mediator of glucocorticoid-induced immunosuppression. interleukin glucocorticoid receptor glucocorticoid-responsive element TPA-responsive element glutathioneS-transferase phorbol myristate acetate glyceraldyhyde-3-phosphate dehydrogenase 3-morpholinopropanesulfonic acid cycloheximide dexamethasone polyacrylamide gel electrophoresis T cell receptor tetracycline doxycycline glucocorticoid-induced leucine zipper Glucocorticoids are potent immunosuppressive agents that inhibit T cell activation and cytokine production. They are used clinically for treatment of autoimmune and inflammatory diseases, such as rheumatoid arthritis and asthma, and for preventing transplant rejection. Glucocorticoids inhibit transcriptional up-regulation of T cell-derived cytokines, such as IL1-2, IL-4, IL-10, and γ-interferon (1Boumpas D.T. Chrousos G.P. Wilder R.L. Cupps T.R. Balow J.E. Ann. Intern. Med. 1993; 119: 1198-1208Crossref PubMed Scopus (653) Google Scholar, 2Gottlicher M. Heck S. Herrlich P. J. Mol. Med. 1998; 76: 480-489Crossref PubMed Scopus (316) Google Scholar, 3Ashwell J.D. Lu F.W. Vacchio M.S. Annu. Rev. Immunol. 2000; 18: 309-345Crossref PubMed Scopus (656) Google Scholar), and proinflammatory cytokines, such as IL-1, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-α. Another target of glucocorticoids in T cells is Fas ligand (FasL), a membrane protein that triggers apoptosis of mature T cells by engaging Fas (4Crispe I.N. Immunity. 1994; 1: 347-349Abstract Full Text PDF PubMed Scopus (122) Google Scholar, 5Yang Y. Mercep M. Ware C.F. Ashwell J.D. J. Exp. Med. 1995; 181: 1673-1682Crossref PubMed Scopus (206) Google Scholar). 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Cell. 1988; Full Text PDF PubMed Scopus Google in with and cells from the and by with the of GILZ by with the was with of the protein with and was with of in at The was from of and S. H. Immunity. 1995; 2: Full Text PDF PubMed Scopus Google Scholar). and doxycycline from containing of the FasL site or containing the site Ashwell J.D. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google and J. Ashwell J.D. Immunity. 2000; 12: Full Text Full Text PDF PubMed Scopus Google and R. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google have been The expression encoding a c-Jun and the reporter driven by of the element from the IL-2 driven by of the element of the IL-2 and driven by of the IL-2 have been D. S.A. M.J. Ashwell J.D. J. Immunol. 1994; Google Scholar). and in expression from of The GILZ was from from cells Cell. Full Text PDF PubMed Scopus Google Scholar). of GILZ from cells from the in the of this gene in a in the acid from a to an This was also found in the T cell as well as cells from and is with the sequences of and GILZ. a C-terminal the was the and of the expression The GILZ from which leucine was by and was the expression The encoding the tetracycline was from encoding by the GILZ and and to and and transient reporter Jurkat cells in of with with the with a and expression to the of DNA used in with phorbol myristate acetate and the of the expression of the constructs, of the and of the reporter was at a of The of the reporter in the to and GILZ was was by electrophoresis through a gel containing and to a membrane was by and was at in and encoding IL-2 and glyceraldyhyde-3-phosphate dehydrogenase used as at in and the to IL-2 the membrane was by in and and for a and glutathioneS-transferase on between the in and at for the with binding by in by electrophoresis through or and with a AP-1, the T cell was for with as as was the binding that was Ashwell J.D. 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Immunity. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). to the by which GILZ we first its effect on FasL induction is at the transcriptional GILZ was in Jurkat T cells with FasL promoter-driven reporter with an expression the FasL reporter to to the was by treatment with and of a the induction in a that GILZ on transcription. This region of the gene contains a of transcription binding that have been in FasL including for to to and NF-κB to Ashwell J.D. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google Scholar, M. O. J. Immunol. PubMed Scopus Google Scholar, J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, K. A. A. J. 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GILZ could its effect on the FasL transcription by preventing of proteins, or could at a for example at the site of binding to the FasL promoter. between the GILZ expression was with reporter driven by the Egr-2 or the promoter and and induction of promoter-driven was blocked by GILZ. transcriptional up-regulation of the FasL promoter was by expression Egr-2 or of GILZ effect on reporter that GILZ with up-regulation of FasL but by preventing the transcriptional induction of Egr-2 and The induction of Egr-2 and by T cell activation is by elements in J. Ashwell J.D. Immunity. 2000; 12: Full Text Full Text PDF PubMed Scopus Google Scholar, R. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google Scholar). the effect of GILZ on expression could be to interference with Jurkat cells with an reporter with or without GILZ and activated with and GILZ inhibited the induction of the reporter elements are found adjacent to binding for AP-1 to as the or TPA-responsive and the of for its binding site is by binding of the and can in cooperative binding to the c-Jun most the of the to A. C. Annu. Rev. Immunol. 1997; PubMed Scopus Google Scholar), with c-Jun and c-Fos L. J.N. A. 1998; PubMed Scopus Google Scholar). as reported D. S.A. M.J. Ashwell J.D. J. Immunol. 1994; Google Scholar), the reporter construct was also inhibited by a of c-Jun to a as GILZ the that GILZ in with the AP-1 of the this a reporter driven by the of the IL-2 promoter D. S.A. M.J. Ashwell J.D. J. Immunol. 1994; Google Scholar, A.C. K. M.J. Science. 1992; PubMed Scopus Google was Jurkat T its induction by and was by GILZ the effect of GILZ on AP-1 GILZ was a tetracycline expression of the protein with the doxycycline its from the of the expression and transcription by the promoter. Jurkat cells with the GILZ expression the and the reporter the presence of the expression and a in which was by the of the was there was a small in activation-induced AP-1 in the of inhibited induction of AP-1 The effect of was by expression of GILZ protein protein of the T cell by the was by in the presence of and but effect on the of the are with a GILZ the of AP-1, which and to expression of Egr-3, and GILZ inhibited activation-induced AP-1 and contains a leucine zipper domain, the was that GILZ with the leucine AP-1 c-Fos and vitro c-Fos or c-Jun to vitro c-Jun is by the with two that may be the of from the region of the containing and also bind was a small of binding of c-Jun and c-Fos to protein by with or two of that have been in Fas ligand J. Ashwell J.D. Immunity. 2000; 12: Full Text Full Text PDF PubMed Scopus Google Scholar), the that the target of GILZ is in AP-1 the site of interaction in of of a of the The of by of the region containing the leucine zipper domain with an c-Fos and c-Jun by the N-terminal of which the leucine zipper c-Fos c-Jun the C-terminal or of the the to with GILZ the leucine zipper, that the of the was the of a for the GILZ leucine zipper to bind c-Fos and the AP-1 bind the domain of GILZ that contains the leucine zipper is that the GILZ leucine zipper is in One to this is to GILZ can leucine GILZ was with GILZ in GILZ to GILZ which of the leucine zipper, the GILZ also to the product of the gene by to in a leucine suggesting that the leucine zipper of GILZ may be for a of leucine The effect of GILZ on the interaction of AP-1 with its target DNA was in an in of a T cell DNA containing a The was for by but an but a the of of the with but an of the of the at least GILZ with the binding of active AP-1 to its DNA. a in which a GILZ with AP-1 and binding to DNA. The in this was that repression of IL-2 by on new protein GILZ could as such an the of GILZ to of the IL-2 promoter was GILZ blocked the and up-regulation of the IL-2 promoter the leucine zipper of GILZ in direct binding to c-Fos or its in the function of GILZ was The GILZ the leucine zipper domain was as as GILZ at the and the IL-2 promoter This indicates that the of GILZ of the leucine a leucine protein is required for GILZ to is that GILZ can function as a Glucocorticoids and in cell such a is to have of the GR transcriptional its effects, in those by other transcription have a of this we that in to to direct between the GR and target transcription glucocorticoid suppression of normal T cell cytokine may also on a from to transcription of a gene whose product can direct interference between the GR and transcriptional has been in glucocorticoid repression of inflammatory such as collagenase and A. S. A. 1994; PubMed Scopus Google Scholar, K. M.L. W. S. W. G. S. A. 1997; PubMed Scopus Google Scholar), which can be by was to for glucocorticoid repression of IL-2 in T on the that of a GR the N-terminal domain was to inhibit the IL-2 promoter J. Exp. Med. 1992; PubMed Scopus Google Scholar). the of the IL-2 promoter was with Jurkat T in which are for example the of the and the of M.J. P. Y. P.L. R.L. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). we have found that activation-induced up-regulation of IL-2 mRNA in Jurkat T cells is blocked by R. and J. D. suggesting that of the IL-2 promoter in Jurkat normal T on an N-terminal to that used by J. Exp. Med. 1992; PubMed Scopus Google has been reported to a in a in Carlstedt-Duke J. Gustafsson J.A. J. Biol. 1990; Full Text PDF PubMed Google Scholar). a GR in the C-terminal zinc that was in and of suppression (20Jonat C. Rahmsdorf H.J. Park K.K. Cato A.C. Gebel S. Ponta H. Herrlich P. Cell. 1990; 62: 1189-1204Abstract Full Text PDF PubMed Scopus Google Scholar), and the GR in treatment with and induction of or of the and to a to that of the GR Carlstedt-Duke J. Gustafsson J.A. J. Biol. 1990; Full Text PDF PubMed Google Scholar). are with the that a gene product could in transcriptional induction of the IL-2 promoter. the genes reported to be by the for a protein to IL-2 induction to be by whose leucine zipper is of transcriptional and whose expression is to cells O. R. S. A. L. G. C. Immunity. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). of GILZ inhibited activation-induced up-regulation of the FasL as well as the of two transcription factors in FasL Egr-2 and of Egr-2 and the of and a site has been in the of gene J. Ashwell J.D. Immunity. 2000; 12: Full Text Full Text PDF PubMed Scopus Google Scholar, R. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google Scholar). elements are composite elements that an site and are termed elements A. C. Annu. Rev. Immunol. 1997; PubMed Scopus Google Scholar). GILZ potently inhibited gene expression driven by an The of the IL-2 promoter on the S. S. A. Biochim. Biophys. Acta. 2000; PubMed Scopus Google Scholar), for the inhibition of the IL-2 promoter that of the The that the GILZ leucine zipper with c-Fos or c-Jun but is of homodimerization implies that GILZ can a in the of a GILZ the leucine zipper that GILZ can function as a The leucine zipper could also with other such as the protein which also has a leucine zipper and can bind GILZ in was on the of the up-regulation of its mRNA by can also be by and transcriptional to a promoter through to the DNA-binding domain of the protein C. J. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). to and of with to have we have found that in Jurkat cells as a transcriptional a to in the and of the IL-2 reporter Thus, is that two leucine can in a to genes in GILZ was found to be in cells from a for a receptor and was the cells activated with R. S. J. 2000; PubMed Scopus Google Scholar). genes encoding transcriptional such as and also in the activated with the that GILZ may as a transcriptional in and of a for GILZ of T the in this that in to direct interference through the in T cells glucocorticoids at least that can bind to and with for the c-Fos and c-Jun expression and for the