Glucocorticoid‐induced leucine zipper (GILZ): a new important mediator of glucocorticoid action

Abstract

Glucocorticoids (GCs) represent the mainstay of current anti-inflammatory and immunosuppressive strategies, mediating effects that mostly result in transcriptional regulation of glucocorticoid receptor target genes. A variety of actions are tied together in the response to GC treatment. Dissecting the beneficial from the detrimental actions in GC therapy is a major challenge in basic research, raising the critical issue of whether a single target gene or gene family might eventually be linked to a specific GC function. Glucocorticoid-induced leucine zipper (GILZ) was originally discovered in studies aimed at characterizing genes targeted by dexamethasone. The first suggestion that GILZ plays an important role in GC immunomodulation came from observations of GILZ up-regulation by GCs, mainly in lymphoid organs, and inhibition of anti-CD3-induced activation and apoptosis. The identification of GILZ interaction with and inhibition of NF-kappaB provided a first molecular mechanistic basis for explaining GILZ effects on T cells. Subsequently, other GILZ targets have been identified, including AP-1, Raf-1, and Ras, all involved in GC effects. The finding that GILZ silencing abrogates the antiproliferative activity of dexamethasone and reduces GC inhibition of cytokine-induced COX-2 expression clearly gained GILZ a distinguished reputation within the critical mediators of GC effects. The multiple functions of GILZ and their potential biological relevance are here reviewed.

Astrocytes are a neural target of morphine action via glucocorticoid receptor‐dependent signaling

“…Members of this group include Tsc22d3 (GILZ, Stojadinovic et al, 2007;Ayroldi and Riccardi, 2009) Other genes may display an astrocyte-specific response to GCs. GR-dependent signaling relies on the cellular context (Leong et al, 2003;Yu et al, 2011), which may be associated with the recruitment of cell-type specific GR coactivators (Grenier et al, 2006).…”

Glucocorticoid-Induced Leucine Zipper (GILZ) Over-Expression in T Lymphocytes Inhibits Inflammation and Tissue Damage in Spinal Cord Injury

“…Moreover, GILZ can interact with Ras-dependent mitogen activated protein kinase pathway, in a monomeric conformation and through its NH2 terminal domain, with consequent inhibition of the downstream pathways, including NF-κB activation [22]. Thus, GILZ inhibits NF-κB by multiple mechanisms and acts as an anti-inflammatory molecule [15,[20][21][22][23][24].…”

L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells

“…GILZ has been studied thoroughly, 18 while the study of L-GILZ has just begun; however, increasing evidence suggests that the two isoforms may exert different functions. Specifically, previous studies indicate that L-GILZ has an exclusive role in the regulation of spermatogenesis, 25 and the present study suggests that L-GILZ may have an exclusive role in the control of p53 activation.…”

“…17 GILZ mediates several anti-inflammatory and immunomodulatory GC functions. [18][19][20][21][22][23] GILZ and L-GILZ bind Ras and contribute to cell differentiation and the control of tumorigenesis. 24,25 Crosstalk between p53 and GCs has been described as either antagonistic or synergistic depending on cell type and environmental context.…”