GILZ as a Regulator of Cell Fate and Inflammation

Abstract

One of the human body’s initial responses to stress is the adrenal response, involving the release of mediators that include adrenaline and glucocorticoids (GC). GC are involved in controlling the inflammatory and immune response mechanisms. Of these, the molecular mechanisms that contribute to anti-inflammatory effects warrant more investigation. Previously, we found that GC induced GILZ (glucocorticoid-induced leucine zipper) quickly and widely in thymocytes, T lymphocytes, and other leukocytes. GILZ regulates the activation of cells and is an essential mediator of endogenous GC and the majority of GC anti-inflammatory effects. Further research in this regard could lead to the development of an anti-inflammatory treatment that yields the therapeutic outcomes of GC but without their characteristic adverse effects. Here, we examine the mechanisms of GILZ in the context of GC. Specifically, we review its role in the proliferation and differentiation of cells and in apoptosis. We also examine its involvement in immune cells (macrophages, neutrophils, dendritic cells, T and B lymphocytes), and in non-immune cells, including cancer cells. In conclusion, GILZ is an anti-inflammatory molecule that could mediate the immunomodulatory activities of GC, with less adverse effects, and could be a target molecule for designing new therapies to treat inflammatory diseases.

Glucocorticoids and COVID-19

“…Among the many actions of both endogenous GCs and their structurally homologous drugs is the control of mechanisms involved in cell growth and survival and consequently of tissue integrity [16] , [18] , [28] . This GC regulatory activity on cell fate is common to all types of cells and organs in the body, which is consistent with the presence of GRs in all cells, the existence of GR recognition elements in all chromosomes [29] , [30] and the GR-mediated regulation of gene trascription in a complex system acting as dimers (homo- or hetero-dimers), monomers or tetramers.…”

“…In addition to the GRs direct interaction with components of the MAPK pathway, GCs can also up-regulate GILZ, which then binds to and inhibits different molecules of the MAPK pathway, such as Ras and the extracellular-signal-regulated kinase (ERK) [29] , [40] . Other example of GC anti-inflammatory activities, mediated by NF-κB, AP-1 and the MAPK pathway, is the inhibition of some cytokine production including IL-6, IFN-γ and TNF [16] .…”

Circadian Clock, Glucocorticoids and NF-κB Signaling in Neuroinflammation- Implicating Glucocorticoid Induced Leucine Zipper as a Molecular Link

“…GILZ is a leucine zipper protein that belongs to the transforming growth factor β-stimulated clone-22 (Tsc22d3) family of transcription factors. GILZ protein binds the transactivation domain of activated p65 and prevents its nuclear translocation ( Cannarile et al, 2001 ; Di Marco et al, 2007 ). Although GILZ and I κ Bα have been shown to inhibit activated NF- κ B in the cytoplasm, little is known about the synchronization or delays in their transcription and subsequent inhibitory functions.…”

“…With six GRE in its promoter, GILZ protein is strongly induced by the GC with varying dynamics in different tissues suggesting that the expression is modulated by local environment with potential effects on cellular responses ( Bruscoli et al, 2021 ). In human and rodents, GILZ is ubiquitously expressed in the brain and spinal cord ( Ayyar et al, 2015 ; Mazzon et al, 2014 ).…”

“…In conclusion, considerable evidence supports GILZ as an anti-inflammatory molecule that inhibits NF- κ B activation and prevents inflammatory cell infiltration, elucidation of its specific role in neurodegenerative processes will help developing novel therapeutics. In this context, GILZ has been suggested as an GC alternative with less potential for adverse effects such as osteoporosis and obesity ( Ayroldi & Riccardi, 2009 ; Bruscoli et al, 2021 ).…”