title: 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-kappa B 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.
authors.affiliation: Laboratory of Immune Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Mittelstadt
authors.forename: J D
authors.initials: JD
authors.lastname: Ashwell
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D051767:Early Growth Response Protein 2; D051776:Early Growth Response Protein 3; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D019169:Jurkat Cells; D016350:Leucine Zippers; D008562:Membrane Glycoproteins / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; C497326:EGR2 protein, human; D051767:Early Growth Response Protein 2; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005938:Glucocorticoids; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; C404226:TSC22D3 protein, human; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D051776:Early Growth Response Protein 3; D003907:Dexamethasone