The Anti-Inflammatory Effect of Glucocorticoids Is Mediated by Glucocorticoid-Induced Leucine Zipper in Epithelial Cells

J Allergy Clin Immunol. 2007 Jan;119(1):115-22. doi: 10.1016/j.jaci.2006.08.027. Epub 2006 Oct 13.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Inflammatory Agents / pharmacology*
  • Cell Line, Transformed
  • Cytokines / pharmacology
  • Dexamethasone / pharmacology*
  • Epithelial Cells / metabolism*
  • Humans
  • NF-kappa B / metabolism
  • RNA, Messenger / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • NF-kappa B
  • RNA, Messenger
  • TSC22D3 protein, human
  • Transcription Factors
  • Dexamethasone