Glucocorticoid-induced leucine zipper (GILZ) is involved in glucocorticoid-induced and mineralocorticoid-induced leptin production by osteoarthritis synovial fibroblasts.

Mustapha Zeddou,Michel G Malaise,Olivier Malaise,Biserka Relic,Edith Charlier,Philippe Gillet,Céline Deroyer,Sophie Neuville,Edouard Louis,Dominique De Seny

doi:10.1186/s13075-016-1119-6

Abstract

BackgroundGlucocorticoid-induced leucine zipper (GILZ) is a mediator of the anti-inflammatory activities of glucocorticoids. However, GILZ deletion does not impair the anti-inflammatory activities of exogenous glucocorticoids in mice arthritis models and GILZ could also mediate some glucocorticoid-related adverse events. Osteoarthritis (OA) is a metabolic disorder that is partly attributed to adipokines such as leptin, and we previously observed that glucocorticoids induced leptin secretion in OA synovial fibroblasts. The purpose of this study was to position GILZ in OA through its involvement in the anti-inflammatory activities of glucocorticoids and/or in the metabolic pathway of leptin induction. The influences of mineralocorticoids on GILZ and leptin expression were also investigated.MethodsHuman synovial fibroblasts were isolated from OA patients during knee replacement surgery. Then, the cells were treated with a glucocorticoid (prednisolone), a mineralocorticoid (aldosterone), a glucocorticoid receptor (GR) antagonist (mifepristone), a selective glucocorticoid receptor agonist (Compound A), mineralocorticoid receptor (MR) antagonists (eplerenone and spironolactone), TNF-α or transforming growth factor (TGF)-β. Cells were transfected with shRNA lentiviruses for the silencing of GILZ and GR. The leptin, IL-6, IL-8 and matrix metalloproteinase (MMP)-1 levels were measured by ELISA. Leptin, the leptin receptor (Ob-R), GR and GILZ expression levels were analyzed by western blotting and/or RT-qPCR.Results(1) The glucocorticoid prednisolone and the mineralocorticoid aldosterone induced GILZ expression dose-dependently in OA synovial fibroblasts, through GR but not MR. Similar effects on leptin and Ob-R were observed: leptin secretion and Ob-R expression were also induced by prednisolone and aldosterone through GR; (2) GILZ silencing experiments demonstrated that GILZ was involved in the glucocorticoid-induced and mineralocorticoid-induced leptin secretion and Ob-R expression in OA synovial fibroblasts; and (3) GILZ inhibition did not alter the production of pro-inflammatory cytokines by OA synovial fibroblast or the anti-inflammatory properties of glucocorticoids.ConclusionsThe absence of GILZ prevents corticoid-induced leptin and Ob-R expression without affecting the anti-inflammatory properties of glucocorticoids in OA synovial fibroblasts. Mineralocorticoids also induce leptin and Ob-R expression through GILZ.

Highlights

Glucocorticoid-induced leucine zipper (GILZ) is a mediator of the anti-inflammatory activities of glucocorticoids
In the present study, we investigated the following issues: (1) whether GILZ expression is induced by mineralocorticoids in human OA synovial fibroblasts and whether this effect is dependent on either glucocorticoid receptor (GR) or mineralocorticoid receptor (MR); (2) whether GILZ and leptin expression are closely correlated; and (3) whether GILZ plays a central role as an anti-inflammatory agent in this type of cell
Prednisolone and aldosterone induced GILZ protein expression through GR in human OA synovial fibroblasts Human OA synovial fibroblasts were stimulated for 5 days with prednisolone (1 μM) or aldosterone (1 or 10 μM)

Summary

Introduction

Glucocorticoid-induced leucine zipper (GILZ) is a mediator of the anti-inflammatory activities of glucocorticoids. The purpose of this study was to position GILZ in OA through its involvement in the anti-inflammatory activities of glucocorticoids and/or in the metabolic pathway of leptin induction. Recent studies have highlighted a major role of GILZ in the anti-inflammatory activities of glucocorticoids. GILZ is expressed by synovial fibroblasts and is an endogenous anti-inflammatory mediator in rheumatoid arthritis [8]. GILZ depletion does not always impair the anti-inflammatory activities of exogenous glucocorticoids [9, 10]. Evidence of a central role of GILZ as an anti-inflammatory agent is lacking and controversial, and requires further exploration, with respect to osteoarthritis (OA), for which intra-articular glucocorticoid injections are used as a symptomatic treatment

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