Glucocorticoid-induced leucine zipper overexpression inhibits lipopolysaccharide-induced retinal inflammation in rats

Gu, Ruiping; Lei, Boya; Shu, Qinmeng; Li, Gang; Xu, Gezhi

doi:10.1016/j.exer.2017.02.011

Cited by 12 publications

(20 citation statements)

References 38 publications

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“…TSC22D3, identified as a glucocorticoid‐transactivated gene that functions as a transcriptional regulator, is known to promote the anti‐inflammatory, immunosuppressive, and anti‐proliferative actions of glucocorticoids in various cells . Overexpression of retinal TSC22D3 protected retinal neurons from light‐induced degeneration and lipopolysaccharide‐induced inflammation . TSC22D3 mainly exerts its effects by homo‐ or hetero‐dimerization with specific partner proteins, including transcription factors such as AP‐1, Raf‐1 and Ras, and regulates the expression of target genes at the transcription level .…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid‐transactivated TSC22D3 attenuates hypoxia‐ and diabetes‐induced Müller glial galectin‐1 expression via HIF‐1α destabilization

Kanda

Hirose

Noda

et al. 2020

J Cellular Molecular Medi

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Galectin-1/LGALS1, a newly recognized angiogenic factor, contributes to the pathogenesis of diabetic retinopathy (DR). Recently, we demonstrated that glucocorticoids suppressed an interleukin-1β-driven inflammatory pathway for galectin-1 expression in vitro and in vivo. Here, we show glucocorticoid-mediated inhibitory mechanism against hypoxia-inducible factor (HIF)-1α-involved galectin-1 expression in human Müller glial cells and the retina of diabetic mice. Hypoxia-induced increases in galectin-1/LGALS1 expression and promoter activity were attenuated by dexamethasone and triamcinolone acetonide in vitro. Glucocorticoid application to hypoxia-stimulated cells decreased HIF-1α protein, but not mRNA, together with its DNA-binding activity, while transactivating TSC22 domain family member (TSC22D)3 mRNA and protein expression. Co-immunoprecipitation revealed that glucocorticoid-transactivated TSC22D3 interacted with HIF-1α, leading to degradation of hypoxia-stabilized HIF-1α via the ubiquitin-proteasome pathway. Silencing TSC22D3 reversed glucocorticoid-mediated ubiquitination of HIF-1α and subsequent down-regulation of HIF-1α and galectin-1/LGALS1 levels. Glucocorticoid treatment to mice significantly alleviated diabetes-induced retinal HIF-1α and galectin-1/Lgals1 levels, while increasing TSC22D3 expression. Fibrovascular tissues from patients with proliferative DR demonstrated co-localization of galectin-1 and HIF-1α in glial cells partially positive for TSC22D3. These results indicate that glucocorticoid-transactivated TSC22D3 attenuates hypoxia-and diabetes-induced retinal glial galectin-1/LGALS1 expression via HIF-1α destabilization, highlighting therapeutic implications for DR in the era of anti-vascular endothelial growth factor treatment. K E Y W O R D S diabetic retinopathy, galectin-1, glucocorticoid, HIF-1α, hypoxia, Müller glia, transactivation, TSC22D3

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Section: Discussionmentioning

confidence: 99%

Glucocorticoid‐transactivated TSC22D3 attenuates hypoxia‐ and diabetes‐induced Müller glial galectin‐1 expression via HIF‐1α destabilization

Kanda

Hirose

Noda

et al. 2020

J Cellular Molecular Medi

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“…The biological activity of a full-length GILZ fusion protein has previously been described [19][20][21][22]. Our previous studies have found that full-length GILZ suppressed ICAM-1 and MCP-1 expression by dephosphorylating NF-κB p65 in retinal endothelial cells in vitro [23] and inhibited LPSinduced retinal inflammation in rats in vivo [10]. The full-length GILZ protein contains 134 amino acids, and its C-terminal region (amino acids 98-134) contains 8 proline (P) residues, 8 glutamic acid (E) residues, and 5 PxxP sequences.…”

Section: Discussionmentioning

confidence: 90%

“…Our team has explored the role of GILZ in inhibiting retinal inflammation. By overexpressing retinal GILZ, we demonstrated [10] that GILZ attenuates the inflammatory response in rats with endotoxin-induced uveitis (EIU). Furthermore, a synthetic GILZ peptide derived from the C-terminal domain of GILZ, which includes 8 proline residues, 8 glutamic acid residues, and 5 PxxP sequences, prevents Müller cell gliosis and inflammatory cytokine secretion [11].…”

Section: Introductionmentioning

confidence: 99%

Synthetic Glucocorticoid-Induced Leucine Zipper Peptide Inhibits Lipopolysaccharide-Induced Ocular Inflammation in Rats

Guo

et al. 2019

Ophthalmic Res

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To demonstrate the anti-inflammatory action of a synthetic glucocorticoid-induced leucine zipper (GILZ 98-134) peptide (GILZ-p) in a model of endotoxin-induced uveitis (EIU) in rats. Methods: The EIU model was induced in Sprague Dawley rats with an intravitreal injection of lipopolysaccharide (LPS). Synthetic GILZ-p was injected intravitreally 6 h after the LPS injection. To evaluate the anti-inflammatory effects of GILZ-p, the inflammatory response in the anterior chamber and iris of the rat eyes was evaluated with a slitlamp microscope on days 0, 1, 2, 3, and 4 after GILZ-p injection. The retinal expression of inflammatory cytokines was measured on days 0, 1, 2, 3, and 4 after GILZ-p injection. Müller cell gliosis was also detected at planned time points after GILZ-p injection. Results: Anterior segment inflammation peaked at 24 h after LPS injection in the EIU model. Compared with the controls, intravitreal GILZ-p significantly suppressed LPS-induced anterior segment inflammation in the EIU rats. The levels of retinal inflammatory factors IL-1β, TNF-α, MCP-1, and ICAM-1 were simultaneously reduced by the intravitreal GILZ-p injection. The expression of vimentin in the EIU retina was significantly reduced by GILZ-p, and the downregulated aquaporin 4 in the EIU retina was significantly restored by GILZ-p. Conclusion: The synthetic GILZ-p inhibited the inflammatory reaction in the EIU model and may have utility in the treatment of inflammatory ocular disease.

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“…However, the exact mechanism by which GCs mediate these effects in the retina has not been clearly determined. Glucocorticoid-induced leucine zipper (GILZ) transcription factor was found to be down-regulated in a rat model of retinal inflammation, in the aqueous humor of human eyes with bacterial endophthalmitis [60], and in lipopolysaccharide (LPS)-treated rat retinal endothelial cells [61], underlying GCs responsiveness in retinal inflammatory diseases. GILZ overexpression suppressed LPS-induced activation of NF-κB and the retinal toll-like receptor4-myeloid differentiation factor 88 (TLR4-MyD88) signaling pathways, which has been shown to play a vital role in the inflammatory response [60].…”

Section: Introductionmentioning

confidence: 99%

“…Glucocorticoid-induced leucine zipper (GILZ) transcription factor was found to be down-regulated in a rat model of retinal inflammation, in the aqueous humor of human eyes with bacterial endophthalmitis [60], and in lipopolysaccharide (LPS)-treated rat retinal endothelial cells [61], underlying GCs responsiveness in retinal inflammatory diseases. GILZ overexpression suppressed LPS-induced activation of NF-κB and the retinal toll-like receptor4-myeloid differentiation factor 88 (TLR4-MyD88) signaling pathways, which has been shown to play a vital role in the inflammatory response [60]. Intravitreal TA injections in an early diabetic rat model significantly activated GR and p38 MAPK signaling pathway, thereby exerted an anti-apoptotic and protective effect on retinal neurons [62].…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid receptor signaling in the eye

2018

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Glucocorticoids (GCs) are essential steroid hormones that regulate numerous metabolic and homeostatic functions in almost all physiological systems. Synthetic glucocorticoids are among the most commonly prescribed drugs for the treatment of various conditions including autoimmune, allergic and inflammatory diseases. Glucocorticoids are mainly used for their potent anti-inflammatory and immunosuppressive activities mediated through signal transduction by their nuclear receptor, the glucocorticoid receptor (GR). Emerging evidence showing that diverse physiological and therapeutic actions of glucocorticoids are tissue-, cell-, and sex-specific, suggests more complex actions of glucocorticoids than previously anticipated. While several synthetic glucocorticoids are widely used in the ophthalmology clinic for the treatment of several ocular diseases, little is yet known about the mechanism of glucocorticoid signaling in different layers of the eye. GR has been shown to be expressed in different cell types of the eye such as cornea, lens, and retina, suggesting an important role of GR signaling in the physiology of these ocular tissues. In this review, we provide an update on the recent findings from in vitro and in vivo studies reported in the last 5 years that aims at understanding the role of GR signaling specifically in the eye. Advances in studying the physiological effects of glucocorticoid in the eye are vital for the elaboration of optimized and targeted GCs therapies with potent anti-inflammatory potential while minimizing adverse effects.

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Glucocorticoid-induced leucine zipper overexpression inhibits lipopolysaccharide-induced retinal inflammation in rats

Cited by 12 publications

References 38 publications

Glucocorticoid‐transactivated TSC22D3 attenuates hypoxia‐ and diabetes‐induced Müller glial galectin‐1 expression via HIF‐1α destabilization

Glucocorticoid‐transactivated TSC22D3 attenuates hypoxia‐ and diabetes‐induced Müller glial galectin‐1 expression via HIF‐1α destabilization

Synthetic Glucocorticoid-Induced Leucine Zipper Peptide Inhibits Lipopolysaccharide-Induced Ocular Inflammation in Rats

Glucocorticoid receptor signaling in the eye

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