The anti-inflammatory effect of glucocorticoids is mediated by glucocorticoid-induced leucine zipper in epithelial cells
The anti-inflammatory effect of glucocorticoids is mediated by glucocorticoid-induced leucine zipper in epithelial cells
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DOI：
10.1016/j.jaci.2006.08.027
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发表时间：
2007-01-01
影响因子：
14.2
通讯作者：
Zuraw, Bruce L.
中科院分区：
文献类型：
--
作者：
Eddleston, Jane;Herschbach, Jack;Zuraw, Bruce L.
背景：核因子κ B （nf - κ B）在哮喘的发病机制中起着关键作用，与炎症细胞因子的产生有关。最近发现的一种抗炎蛋白，糖皮质激素诱导的亮氨酸拉链（GILZ），可干扰T细胞和巨噬细胞中nf - κ b介导的基因转录。目的：分析GILZ在气道上皮细胞中的表达调控，确定GILZ是否介导了皮质类固醇的部分抗炎作用。方法：采用PCR和免疫印迹法检测人上皮细胞在基线和地塞米松或细胞因子（IL-1 β、tnf - α和ifn - γ）刺激后的GILZ表达。在过表达GILZ的BEAS-2B细胞中评估GILZ对LPS-、IL-1 β -和多肌苷：多胞酸诱导的NF-kappa B活化的影响。通过小干扰RNA （small interfering RNA, siRNA）技术下调GILZ的表达，评估了GILZ对地塞米松抑制作用的要求。结果：GILZ在人气道上皮细胞中组成性表达，其表达水平在地塞米松作用下升高，在炎性细胞因子作用下降低。BEAS-2B细胞中GILZ的过表达显著抑制了IL-1 β、LPS和多肌苷：多胞酸激活nf - κ B的能力，而GILZ的下调抑制了地塞米松抑制IL-1 β诱导的趋化因子表达的能力。结论：本研究证实了GILZ在人气道上皮细胞中的表达、地塞米松对其的诱导作用、炎症细胞因子对其的抑制作用以及介导地塞米松抗炎作用的作用。临床意义：治疗性上调GILZ可能是治疗哮喘的一种新策略。
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.