Inhibition of AP-1 by the glucocorticoid-inducible protein GILZ.
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.
Mesh Terms:
DNA-Binding Proteins, Dexamethasone, Early Growth Response Protein 2, Early Growth Response Protein 3, Fas Ligand Protein, Gene Expression Regulation, Glucocorticoids, Humans, Interleukin-2, Jurkat Cells, Leucine Zippers, Membrane Glycoproteins, NF-kappa B, NFATC Transcription Factors, Nuclear Proteins, Promoter Regions, Genetic, T-Lymphocytes, Transcription Factor AP-1, Transcription Factors, Transcription, Genetic
DNA-Binding Proteins, Dexamethasone, Early Growth Response Protein 2, Early Growth Response Protein 3, Fas Ligand Protein, Gene Expression Regulation, Glucocorticoids, Humans, Interleukin-2, Jurkat Cells, Leucine Zippers, Membrane Glycoproteins, NF-kappa B, NFATC Transcription Factors, Nuclear Proteins, Promoter Regions, Genetic, T-Lymphocytes, Transcription Factor AP-1, Transcription Factors, Transcription, Genetic
J. Biol. Chem.
Date: Aug. 03, 2001
PubMed ID: 11397794
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