[GILZ (glucocorticoid-induced leucine zipper), a mediator of the anti-inflammatory and immunosuppressive activity of glucocorticoids].
Glucocorticoids (GCs) are widely used in therapy as anti-inflammatory and immunosuppressive drugs. Their effects are the result of a number of genomic and non-genomic mechanisms including regulation of gene transcription. In fact, GCs through interaction with the glucocorticoid receptor (GR) regulate transcription of a number of target genes. Induction and/or inhibition of gene expression are responsible for the therapeutic effects of GC as well of unwanted side effects that can limit their therapeutic use. Dissecting the molecular mechanisms responsible for beneficial and/or detrimental actions of GC is an important challenge in basic research. In particular, a critical issue is to establish how a single gene might eventually be linked to a specific GC-induced effect. We identified GILZ (glucocorticoid-induced leucine zipper), a gene rapidly activated by dexamethasone, during studies aimed at characterizing gene(s) activated by GCs. The first experimental evidence indicating GILZ as a player in the GC-induced immunomodulation comes from observation that GILZ up-regulation in Tlymphocytes inhibits anti-CD3-induced activation/proliferation and apoptotic cell death. We then found that GILZ interacts with and inhibits NF-icB. Subsequently, this observation has been confirmed in many other laboratories and other GILZ targets have been identified, including AP-1, Raf-1, and Ras, all involved in GC effects. Notably, GILZ inhibition by silencing counters the anti-proliferative activity of dexamethasone and reduces GC-mediated inhibition of COX-2 expression. All these effects suggest GILZ as a mediator of the anti-inflammatory/immunosuppressive activity of GCs.
Riccardi
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Società Italiana di Farmacologia e Ordinario di Farmacologia, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia. riccardi@unipg.it
D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use*; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000188:drug therapy*; D016350:Leucine Zippers / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D005938:Glucocorticoids; C404226:TSC22D3 protein, human; D014157:Transcription Factors