Divergent Effects of Endogenous and Exogenous Glucocorticoid‐Induced Leucine Zipper in Animal Models of Inflammation and Arthritis

Abstract

Objective. Glucocorticoid-induced leucine zipper (GILZ) has effects on inflammatory pathways that suggest it to be a key inhibitory regulator of the immune system, and its expression is exquisitely sensitive to induction by glucocorticoids. We undertook this study to test our hypothesis that GILZ deficiency would exacerbate experimental immune-mediated inflammation and impair the effects of glucocorticoids on inflammation and, correspondingly, that exogenous GILZ would inhibit these events.Methods. GILZ ؊/؊ mice were generated using the Cre/loxP system, and responses were studied in delayedtype hypersensitivity (DTH), antigen-induced arthritis (AIA), K/BxN serum-transfer arthritis, and lipopolysaccharide (LPS)-induced cytokinemia. Therapeutic expression of GILZ via administration of recombinant adeno-associated virus expressing the GILZ gene (GILZ-rAAV) was compared to the effects of glucocorticoid in collagen-induced arthritis (CIA).Results. Increased T cell proliferation and DTH were observed in GILZ ؊/؊ mice, but neither AIA nor K/BxN serum-transfer arthritis was affected, and GILZ deficiency did not affect LPS-induced cytokinemia. Deletion of GILZ did not impair the effects of exogenous glucocorticoids on CIA or cytokinemia. In contrast, overexpression of GILZ in joints significantly inhibited CIA, with an effect similar to that of dexamethasone. Conclusion. Despite effects on T cell activation, GILZ deficiency had no effect on effector pathways of arthritis and was unexpectedly redundant with effects of glucocorticoids. These findings do not support the hypothesis that GILZ is central to the actions of glucocorticoids, but the efficacy of exogenous GILZ in CIA suggests that further evaluation of GILZ in inflammatory disease is required.

The Role and Effects of Glucocorticoid-Induced Leucine Zipper in the Context of Inflammation Resolution

“…However, GILZ KO mice did not present difference in severity of inflammation as compared with WT mice in a model of arthritis (13), although GILZ treatment using an adenoviral strategy was therapeutically effective. This latter study (13) is in agreement with our findings using LPS-induced inflammation, showing that absence of GILZ does not modify the severity or course of natural resolution of inflammation, but that an exogenous GILZ-based strategy efficiently resolves acute inflammation. Taken together, these studies indicate that GILZ may affect differently the outcome of inflammation resolution in different experimental models, possibly due to the fact that GILZ and AnxA1 influence each other's expression.…”

“…For instance, TAT-GILZ administration promoted a protective effect in a model of inflammatory bowel disease (9) and spinal cord injury (12). Moreover, recent studies showed that GILZ overexpression inhibits endothelial cell adhesion function (42) and protects against endotoxemia (43) and arthritis (13).…”

“…These mechanisms are thought to be important for their ability to attenuate inflammation (8). GILZ appears to have a physiological role in the regulation of inflammatory mechanisms; however, there are few reports that explore its role in inflammatory disease (9)(10)(11)(12)(13).…”

“…Male BALB/c mice (8-10 wk) bred in the Animal Facility of Centro de Bioterismo of Universidade Federal de Minas Gerais (Brazil) were housed under standard conditions and had free access to commercial chow and water. GILZ-deficient male mice were generated as described (13), and C57BL/6 littermates were bred in the animal facility of the Immunopharmacology Laboratory.…”

Exclusive transmission of the embryonic stem cell‐derived genome through the mouse germline

“…Males hemizygous for a knockout mutation in Tsc22d3 , from three independently generated strains (Bruscoli et al ., 2012; Ngo et al ., 2013a, 2013b; Romero et al ., 2012; Suarez et al ., 2012), are sterile due to the inability of spermatocytes to complete the first meiotic division. A few weeks after birth, hemizygous Tsc22d3 knockout males display Sertoli‐cell‐only seminiferous tubuli, which are totally devoid of germ cells.…”