Abstract
Glucocorticoids (GCs) are the most commonly used drugs for treatment of autoimmune and inflammatory diseases. Their efficacy is due to their ability to bind cytoplasmic receptors (glucocorticoid receptors, GR) and other cytoplasmic proteins, thus regulating gene expression. Although GCs are potent life-saving drugs, their therapeutic effects are transitory and chronic use of GCs is accompanied by serious side effects. Therefore, new drugs are needed to replace GCs. We have identified a gene, glucocorticoid-induced leucine zipper (GILZ or tsc22d3), that is rapidly and invariably induced by GCs. Human GILZ is a 135-amino acid protein that mediates many GC effects, including inhibition of the NF-κB and MAPK pathways. Similar to GCs, GILZ exerts anti-inflammatory activity in experimental disease models, including inflammatory bowel diseases and arthritis. While transgenic mice that overexpress GILZ are more resistant, GILZ knockout mice develop worse inflammatory diseases. Moreover, the anti-inflammatory effect of GCs is attenuated in GILZ-deficient mice. Importantly, in vivo delivery of recombinant GILZ protein cured colitis and facilitated resolution of lipopolysaccharide-induced inflammation without apparent toxic effects. A synthetic GILZ-derived peptide, corresponding to the GILZ region that interacts with NF-κB, was able to suppress experimental autoimmune encephalomyelitis. Collectively, these findings indicate that GILZ is an anti-inflammatory molecule that may serve as the basis for designing new therapeutic approaches to inflammatory diseases.
Highlights
INTRODUCTIONGLUCOCORTICOID-INDUCED LEUCINE ZIPPER (GILZ) IS A GLUCOCORTICOID (GC)-INDUCIBLE GENE
GLUCOCORTICOID-INDUCED LEUCINE ZIPPER (GILZ) IS A GLUCOCORTICOID (GC)-INDUCIBLE GENEGlucocorticoids (GCs) are important hormones able to regulate homeostasis of virtually all organs and tissues of the human body
In the THP-1 macrophage cell line, GILZ binds to the p65/NF-κB subunit and inhibits the expression of costimulatory molecules CD80 and CD86 and the production of chemokines Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) and Macrophage inflammatory protein 1 (MIP-1), mimicking the effect of GC treatment on macrophages (Berrebi et al, 2003)
Summary
GLUCOCORTICOID-INDUCED LEUCINE ZIPPER (GILZ) IS A GLUCOCORTICOID (GC)-INDUCIBLE GENE. GILZ is involved in the modulation of the same signaling immune responses and inflammation-related pathways implicated in GCinduced anti-inflammatory and immunosuppressive activities (Figure 1), suggesting that targeting GILZ can constitute a new approach to the treatment of inflammatory/autoimmune diseases. Ayroldi et al (2001) demonstrated that GILZ directly binds to NF-κB and inhibits its activation (Figure 2) They showed that GILZ overexpression blocks nuclear translocation of the NF-κB/p65 subunit and it prevents the induction of pro-inflammatory NF-κB target genes in thymocytes, for example Interleukin-2 (IL-2) (Ayroldi et al, 2001; Di Marco et al, 2007). In the THP-1 macrophage cell line, GILZ binds to the p65/NF-κB subunit and inhibits the expression of costimulatory molecules CD80 and CD86 and the production of chemokines Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) and Macrophage inflammatory protein 1 (MIP-1), mimicking the effect of GC treatment on macrophages (Berrebi et al, 2003). GILZ overexpression inhibits endothelial cell adhesive function through decreased expression of E-selectin, Intercellular Adhesion Molecule 1 (ICAM-1), C-C Motif
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