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


CONCLUSIONS
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.


CONCLUSIONS
Therapeutic upregulation of GILZ may be a novel strategy for the treatment of asthma.
Eddleston
Jane
J
Veterans Medical Research Foundation, La Jolla, CA, USA. jeddleston@vapop.ucsd.edu
Herschbach
Jack
J
Wagelie-Steffen
Amy L
AL
Christiansen
Sandra C
SC
Zuraw
Bruce L
BL
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D016207:Cytokines / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D003907:Dexamethasone