Glucocorticoid-Induced Leucine Zipper as a Druggable Target in Inflammatory Bowel Diseases

Abstract

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.

Gender May Influence the Immunosuppressive Actions of Prednisone in Young Patients With Inflammatory Bowel Disease

“…The role of GILZ has been studied in several mouse models of IBD using dinitrobenzene sulfonic acid-induced colitis ( 40 ). In particular, the severity of colonic inflammation was diminished in transgenic mice overexpressing GILZ and exacerbated in GILZ-conditional knock-out mice with a T-cell specific GILZ deletion highlighting its anti-inflammatory effects that mimic those of GCs ( 41 , 42 ).…”

Long Term Delta-9-tetrahydrocannabinol Administration Inhibits Proinflammatory Responses in Minor Salivary Glands of Chronically Simian Immunodeficieny Virus Infected Rhesus Macaques

“…Out of these, 256 and 200 genes were successfully annotated in the VEH-untreated/SIV and THC/SIV groups, respectively. At least five genes with well-established functions in maintaining oral epithelial barrier integrity AGR2 [ 58 , 59 ], WFDC2 [ 60 , 61 ], anti-inflammatory function ( TSC22D3 ) [ 62 , 63 , 64 ] and prevention of oxidative stress [ 48 , 65 ] were found to be significantly downregulated in OPM of VEH-untreated/SIV rhesus macaques ( Figure 1 D). On the other hand, proinflammatory extracellular matrix degrading proteinases ( MMP7 ) [ 66 ], endoplasmic reticulum (ER) stress regulating and anti-viral CREB3L1 [ 67 ] and DNA demethylating APOBEC2 [ 68 ] were significantly downregulated in OPM of THC/SIV rhesus macaques ( Figure 1 D).…”

“…Further, WFDC2 is expressed by MiSGs [ 60 , 61 ] and in association with other related WAP domain containing proteins functions in epithelial host defense. Finally, the expression of TSC22D3 , also known as glucocorticoid induced leucine zipper ( GILZ ), is stimulated by glucocorticoids and IL10 and is well described to play a key role in mediating the anti-inflammatory and immunosuppressive effects of both proteins [ 62 , 63 , 64 ].…”

“…The decreased mRNA expression of WFDC2 and TSC22D3 was equally intriguing as both proteins play important roles in inhibiting metalloprotease activity, mucosal inflammation and maintaining the intestinal epithelial barrier function and by extension the oral epithelial barrier integrity [ 60 , 61 , 62 , 63 , 64 ]. Similar to AGR2 , protein expression of both WFDC2 ( Figure 3 ) and TSC22D3 ( Figure 4 ) localized exclusively to the MiSG acini and salivary ducts.…”

A Glance at the Use of Glucocorticoids in Rare Inflammatory and Autoimmune Diseases: Still an Indispensable Pharmacological Tool?

“…GILZ can inhibit NF-κB, a pivotal transcription factor in the regulation of pro-inflammatory cytokines, thereby contributing to the regulation of the CD4+ response in the gut ( 79 ). In the same model of colitis, but in a different strain of genetically modified mice, the GILZ B cell-conditional knock-out mice (GILZ B cKO), 3 day-treatment with the recombinant TAT-GILZ protein reversed the symptoms of DNBS-induced colitis, similar to wild-type mice ( 80 , 81 ). In the context of a neutrophilic inflammation in a model of LPS-induced pleurisy in mice, TAT-GILZ was able to lead to inflammation resolution by decreasing cytokine production and promoting apoptosis in neutrophils ( 82 ).…”