The anti-inflammatory effect of glucocorticoids is mediated by glucocorticoid-induced leucine zipper in epithelial cells

Background: Nuclear factor kappa B (NF-kappa B) plays a key role in the pathogenesis of asthma, being linked to the production of inflammatory cytokines that drive inflammation. A recently described anti-inflammatory protein, glucocorticoid-induced leucine zipper (GILZ), interferes with NF-kappa B-mediated gene transcription in T cells and macrophages. Objective: We sought to analyze the regulation of GILZ expression in airway epithelial cells and determine whether GILZ mediates part of the anti-inflammatory effect of corticosteroids. Methods: GILZ expression was assessed by means of PCR and immunoblotting in human epithelial cells at baseline and after stimulation with dexamethasone or cytokines (IL-1 beta, TNF-alpha, and IFN-gamma). The effect of GILZ on LPS-, IL-1 beta-, and polyinosinic:polycytidylic acid-induced NF-kappa B activation was assessed in BEAS-2B cells overexpressing GILZ. The requirement for GILZ in the inhibitory action of dexamethasone was assessed by knocking down GILZ expression by means of small interfering RNA (siRNA) technology. Results: GILZ is constitutively expressed by human airway epithelial cells, and its levels are increased by dexamethasone and decreased by inflammatory cytokines. Overexpression of GILZ in BEAS-2B cells significantly inhibited the ability of IL-1 beta, LPS, and polyinosinic:polycytidylic acid to activate NF-kappa B, whereas knockdown of GILZ inhibited the ability of dexamethasone to suppress IL-1 beta-induced chemokine expression. Conclusion: This study demonstrates the expression of GILZ in human airway epithelial cells, its induction by dexamethasone, its suppression by inflammatory cytokines, and its role in mediating the anti-inflammatory effects of dexamethasone. Clinical implications: Therapeutic upregulation of GILZ may be a novel strategy for the treatment of asthma.