Glucocorticoid-induced leucine zipper is downregulated in human alveolar macrophages upon Toll-like receptor activation
Glucocorticoid-induced leucine zipper is downregulated in human alveolar macrophages upon Toll-like receptor activation
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DOI：
10.1002/eji.201142081
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发表时间：
2012-05-01
影响因子：
5.4
通讯作者：
Kiemer, Alexandra K.
中科院分区：
文献类型：
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作者：
Hoppstaedter, Jessica;Diesel, Britta;Kiemer, Alexandra K.
糖皮质激素诱导的亮氨酸拉链（GILZ）的糖皮质激素的诱导在其抑制作用中起作用，而GILZ的表达在炎症条件下减少。然而，在炎症过程中调节GILZ表达的机制尚未被表征。在这里，我们研究了GILZ在人肺泡巨噬细胞（AM）Toll样受体（TLR）激活后的表达。巨噬细胞显示主要表达GILZ转录变体2。脂多糖处理的AM、THP-1细胞和暴露于脂多糖的小鼠的肺显示GILZ蛋白和mRNA水平降低。该效应严格依赖于衔接分子MyD 88，如通过使用特异性配体或敲低策略所示。通过GILZ敲低进行的GILZ下调的功能意义的调查揭示了促炎反应，如增加的细胞因子表达和NF-？B活性。我们发现TLR激活降低了GILZ mRNA的稳定性，这是通过GILZ 3 '-非翻译区介导的。最后，参与的mRNA结合蛋白tristetraprolin（TTP）的建议，因为TTP过表达或敲低调制GILZ的表达和TTP诱导的MyD 88依赖的方式。总之，我们的数据显示TLR激活后，人巨噬细胞中MyD 88和TTP依赖性GILZ下调。GILZ的抑制由mRNA不稳定介导，这可能代表巨噬细胞活化中的调节机制。
Induction of the glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids plays a role in their antiinflammatory action, whereas GILZ expression is reduced under inflammatory conditions. The mechanisms regulating GILZ expression during inflammation, however, have not yet been characterized. Here, we investigated GILZ expression in human alveolar macrophages (AMs) following Toll-like receptor (TLR) activation. Macrophages were shown to predominantly express GILZ transcript variant 2. Lipopolysaccharide-treated AMs, THP-1 cells, and lungs of lipopolysaccharide-exposed mice displayed decreased GILZ protein and mRNA levels. The effect was strictly dependent on the adapter molecule MyD88, as shown by using specific ligands or a knockdown strategy. Investigations on the functional significance of GILZ downregulation performed by GILZ knockdown revealed a proinflammatory response, as indicated by increased cytokine expression and NF-?B activity. We found that TLR activation reduced GILZ mRNA stability, which was mediated via the GILZ 3'-untranslated region. Finally, involvement of the mRNA-binding protein tristetraprolin (TTP) is suggested, since TTP overexpression or knockdown modulated GILZ expression and TTP was induced in a MyD88-dependent fashion. Taken together, our data show a MyD88- and TTP-dependent GILZ downreg-ulation in human macrophages upon TLR activation. Suppression of GILZ is mediated by mRNA destabilization, which might represent a regulatory mechanism in macrophage activation.