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J Allergy Clin Immunol. 2007 Jan;119(1):115-22. Epub 2006 Oct 13.

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

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  • 1Veterans Medical Research Foundation, La Jolla, CA, USA. jeddleston@vapop.ucsd.edu

Abstract

BACKGROUND:

Nuclear factor kappaB (NF-kappaB) 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-kappaB-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-1beta, TNF-alpha, and IFN-gamma). The effect of GILZ on LPS-, IL-1beta-, and polyinosinic:polycytidylic acid-induced NF-kappaB 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-1beta, LPS, and polyinosinic:polycytidylic acid to activate NF-kappaB, whereas knockdown of GILZ inhibited the ability of dexamethasone to suppress IL-1beta-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.

[PubMed - indexed for MEDLINE]
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