Role of transcriptional coregulator GRIP1 in the anti-inflammatory actions of glucocorticoids
Role of transcriptional coregulator GRIP1 in the anti-inflammatory actions of glucocorticoids
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DOI：
10.1073/pnas.1206059109
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发表时间：
2012-07-17
影响因子：
11.1
通讯作者：
Rogatsky, Inez
中科院分区：
文献类型：
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作者：
Chinenov, Yurii;Gupte, Rebecca;Rogatsky, Inez
糖皮质激素受体（GR）对细胞因子基因表达的抑制作用是糖皮质激素抗炎作用的重要组成部分，但其分子机制尚不清楚。在这里，我们报告，糖皮质激素抑制细胞因子基因在初级巨噬细胞介导的GR相互作用蛋白（GRIP）1，转录辅助调节的p160家族，这是招聘到p65占据的基因组NF κ B结合位点与配体GR。我们创建了一个小鼠品系，使条件造血细胞限制性删除GRIP1在成年动物。在该模型中，巨噬细胞中GRIP1耗竭以剂量依赖性方式减弱GR对NF κ B B靶基因的抑制，而与负责其激活的上游Toll样受体途径无关。此外，全基因组转录组分析显示，GRIP 1缺失的巨噬细胞中脂多糖（LPS）诱导的糖皮质激素敏感性靶点广泛去抑制，而不影响其被LPS激活。一致地，相对于野生型，条件性GRIP1缺陷小鼠对全身炎症激发敏感，从而产生LPS诱导的休克的特征性体征。因此，GRIP1作为GR辅阻遏物，促进了糖皮质激素在体内的抗炎作用。
Inhibition of cytokine gene expression by the hormone-activated glucocorticoid receptor (GR) is the key component of the anti-inflammatory actions of glucocorticoids, yet the underlying molecular mechanisms remain obscure. Here we report that glucocorticoid repression of cytokine genes in primary macrophages is mediated by GR-interacting protein (GRIP) 1, a transcriptional coregulator of the p160 family, which is recruited to the p65-occupied genomic NF kappa B-binding sites in conjunction with liganded GR. We created a mouse strain enabling a conditional hematopoietic cell-restricted deletion of GRIP1 in adult animals. In this model, GRIP1 depletion in macrophages attenuated in a dose-dependent manner repression of NF kappa B target genes by GR irrespective of the upstream Toll-like receptor pathway responsible for their activation. Furthermore, genome-wide transcriptome analysis revealed a broad derepression of lipopolysaccharide (LPS)-induced glucocorticoid-sensitive targets in GRIP1-depleted macrophages without affecting their activation by LPS. Consistently, conditional GRIP1-deficient mice were sensitized, relative to the wild type, to a systemic inflammatory challenge developing characteristic signs of LPS-induced shock. Thus, by serving as a GR corepressor, GRIP1 facilitates the anti-inflammatory effects of glucocorticoids in vivo.