Role of GILZ in immune regulation, glucocorticoid actions and rheumatoid arthritis
Center for Inflammatory Disease, Monash University Department of Medicine, Monash Medical Center, Block E Level 5, 246 Clayton Road, Clayton, VIC 3168, Australia. Nature Reviews Rheumatology
(Impact Factor: 9.85).
06/2011; 7(6):340-8. DOI: 10.1038/nrrheum.2011.59
Glucocorticoids have been exploited therapeutically for more than six decades through the use of synthetic glucocorticoids as anti-inflammatory agents, and are still used in as many as 50% of patients suffering from inflammatory diseases such as rheumatoid arthritis (RA). Better understanding of the mechanisms of action of glucocorticoids could enable the development of therapies that dissociate the broad-spectrum benefits of glucocorticoids from their adverse metabolic effects. The glucocorticoid-induced leucine zipper protein (GILZ; also known as TSC22 domain family protein 3) is a glucocorticoid-responsive molecule whose interactions with signal transduction pathways, many of which are operative in RA and other inflammatory diseases, suggest that it is a key endogenous regulator of the immune response. The overlap between the observed effects of GILZ on the immune system and those of glucocorticoids strongly suggest GILZ as a critical mediator of the therapeutic effects of glucocorticoids. Observations of the immunomodulatory effects of GILZ in human RA synovial cells, and in an in vivo model of RA, support the hypothesis that GILZ is a key glucocorticoid-induced regulator of inflammation in RA. Moreover, evidence that the effect of GILZ on bone loss might be in contrast to those of glucocorticoids suggests manipulation of GILZ as a potential means of dissociating the beneficial anti-inflammatory effects of glucocorticoids from their negative metabolic repercussions.
Available from: Simona Ronchetti
- "GILZ is one of the earliest and rapidly induced gene by glucocorticoids (GCs), mainly in lymphoid cells, which regulates activation and apoptosis. Evidence is accumulating that GILZ is an important mediator of GC anti-inflammatory effects in cell lineages and in inflammatory mouse models, through inhibition of the expression of pro-inflammatory genes      . This effect depends on the ability of GILZ to homo-and hetero-dimerize, thereby acting as a regulator of gene transcription. "
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ABSTRACT: Glucocorticoid-Induced Leucine Zipper (GILZ) is a glucocorticoid-inducible gene that mediates glucocorticoid anti-inflammatory effects. GILZ and the isoform L-GILZ are expressed in a variety of cell types, especially of hematopoietic origin, including macrophages, lymphocytes and epithelial cells, and strongly upregulated upon glucocorticoid treatment. A quantitative analysis of GILZ expression in mouse tissues is technically difficult to perform because of the presence of a pseudogene and the high homology of GILZ gene with other genes of TSC22 family. We here propose specific primer pairs to be used in Real Time PCR to avoid unwanted amplification of GILZ pseudogene and TSC-22 family member d1iso3. These primer pairs were used to determine GILZ and L-GILZ expression, in either untreated or in vivo and in vitro dexamethasone-treated tissues. Results indicate that GILZ and L-GILZ are upregulated by glucocorticoids, being GILZ more sensitive to glucocorticoid induction than L-GILZ, but they are differently expressed in all examined tissues, confirming a different role in specific cells. An inappropriate primer pair amplified also GILZ pseudogene and TSC22d1iso3, thus producing misleading results. This quantitative evaluation may be used to better characterize the role of GILZ and L-GILZ in mice and may be translated to humans.
Available from: Chengxue Qin
- "Recognized contributing mechanisms to the anti-inflammatory actions of GCs include the GC-induced anti-inflammatory proteins MAPK phosphatase-1 (MKP1, or DUSP1) and GC-induced leucine zipper (GILZ) (Clark, 2007; Beaulieu & Morand, 2011; Clark & Belvisi, 2012; Newton, 2014; Vandevyver et al., 2013). Previous studies have shown that the anti-inflammatory GC effects (including attenuation of proinflammatory cytokine interleukin (IL)-6 expression, and induction of anti-inflammatory protein MKP-1) are dependent on ANX-A1 (Yang et al., 2006). "
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ABSTRACT: Myocardial infarction (MI) and its resultant heart failure remains a major cause of death in the world. The current treatments for patients with MI are revascularization with thrombolytic agents or interventional procedures. These treatments have focused on restoring blood flow to the ischemic tissue to prevent tissue necrosis and preserve organ function. The restoration of blood flow after a period of ischemia, however, may elicit further myocardial damage, called reperfusion injury. Pharmacological interventions, such as antioxidant and Ca(2+) channel blockers, have shown premises in experimental settings; however, clinical studies have shown limited success. Thus, there is a need for the development of novel therapies to treat reperfusion injury. The therapeutic potential of glucocorticoid-regulated anti-inflammatory mediator annexin-A1 (ANX-A1) has recently been recognized in a range of systemic inflammatory disorders. ANX-A1 binds to and activates the family of formyl peptide receptors (G protein-coupled receptor family) to inhibit neutrophil activation, migration and infiltration. Until recently, studies on the cardioprotective actions of ANX-A1 and its peptide mimetics (Ac2-26, CGEN-855A) have largely focused on its anti-inflammatory effects as a mechanism of preserving myocardial viability following I-R injury. Our laboratory provided the first evidence of the direct protective action of ANX-A1 on myocardium, independent of inflammatory cells in vitro. We now review the potential for ANX-A1 based therapeutics to be seen as a "triple shield" therapy against myocardial I-R injury, limiting neutrophil infiltration and preserving both cardiomyocyte viability and contractile function. This novel therapy may thus represent a valuable clinical approach to improve outcome after MI.
Copyright © 2014. Published by Elsevier Inc.
Available from: Yuan Yang
- "The effects of the GC/GR complex depend on a combination of several effects. These include (i) transrepression, whereby the GC-GR complex tethers to pro-inflammatory transcription factors such as NF-κB and AP-1, constraining their activity; (ii) cis-repression, whereby the GC-GR complex binds directly to DNA and exerts inhibitory effects on gene transcription; and (iii) transactivation, whereby a GC-GR dimer acts as a bona fides transcription factor and activates gene transcription (McKay and Cidlowski, 1999; De Bosscher et al., 2003; Barnes, 2006; Beaulieu and Morand, 2011). Despite their beneficial effects, adverse effects of GC treatment have been noted since the beginning of their usage, because the amount of GCs required therapeutically to inhibit the immune system is in excess of metabolic homeostatic requirements. "
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ABSTRACT: Glucocorticoids (GC) are the most commonly prescribed medications for patients with inflammatory diseases, despite their well-known adverse metabolic effects. Previously, it was understood that the anti-inflammatory effects of the GC/GC receptor (GR) complex were mediated via transrepression, whilst the adverse metabolic effects were mediated via transactivation. It has recently become clear that this "divergent actions" paradigm of GC actions is likely insufficient. It has been reported that the GC/GR-mediated transactivation also contributes to the anti-inflammatory actions of GC, via up-regulation of key anti-inflammatory proteins. One of these is glucocorticoid-induced leucine zipper (GILZ), which inhibits inflammatory responses in a number of important immune cell lineages in vitro, as well as in animal models of inflammatory diseases in vivo. This review aims to compare the GILZ and GC effects on specific cell lineages and animal models of inflammatory diseases. The fact that the actions of GILZ permit a GILZ-based gene therapy to lack GC-like adverse effects presents the potential for development of new strategies to treat patients with inflammatory diseases.
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