Role of transcriptional coregulator GRIP1 in the anti-inflammatory actions of glucocorticoids

Abstract

Inhibition of cytokine gene expression by the hormone-activated glucocorticoid receptor (GR) is the key component of the antiinflammatory 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 NFκB-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 NFκB 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.inflammation | macrophage transcriptome | transcriptional regulation | coactivators | corepressors

Glucocorticoid receptor represses proinflammatory genes at distinct steps of the transcription cycle

“…1 A and B). Consistent with the direct transcriptional effects of GR on inflammatory genes, repression by Dex was recapitulated fully at the level of unprocessed nascent transcripts and was refractory to the protein synthesis inhibitors cycloheximide or puromycin (21).…”

“…We recently established that GRIP1, a cofactor of the p160 coactivator family, is recruited to the NF-κB:GR repression complexes and functions as a corepressor (21). Indeed, GR-mediated repression of numerous inflammatory targets, including genes of both classes, was attenuated in GRIP1-depleted BMMΦ (GRIP1 KD) (21). Interestingly, the elongation-controlled genes TNF, CCL3, and CCl2 were derepressed dramatically in GRIP1 KD MΦ (Fig.…”

“…The putative corepressors mediating glucocorticoid repression at tethering elements have remained enigmatic for many years. We recently established that GRIP1, a cofactor of the p160 coactivator family, is recruited to the NF-κB:GR repression complexes and functions as a corepressor (21). Indeed, GR-mediated repression of numerous inflammatory targets, including genes of both classes, was attenuated in GRIP1-depleted BMMΦ (GRIP1 KD) (21).…”

“…Recently, we reported the identification of the GR-interacting protein-1 (GRIP1), a cofactor of the p160 family known to function as NR coactivators in other contexts, as a GR ligand-dependent corepressor at GR:NF-κB complexes (21). Despite the emerging pivotal role of GRIP1 in suppressing the transcription of numerous proinflammatory genes in vitro and in vivo (21), the molecular targets of the GR:GRIP1 repression complexes remain unknown. Here, we use molecular and genetic methods to assess the mechanisms of GR-mediated repression at inflammatory genes representing distinct transcriptional classes and the contribution of GRIP1 to their regulation.…”

Hic-5 is a transcription coregulator that acts before and/or after glucocorticoid receptor genome occupancy in a gene-selective manner

“…Second, Hic-5 depletion had dramatic effects on Dexregulated transcription of some genes, in which Hic-5 served as an all-or-none switch, so that Dex-induced transcriptional regulation by GR was completely dependent on the presence of Hic-5 for some genes and on the absence of Hic-5 for other genes. In contrast, depletion studies with many other coregulators have indicated that they serve as modulators rather than as all-or-none determinants of steroid hormone-regulated gene expression (2,(36)(37)(38)(39). Third, Hic-5 was able to function as a coactivator and as a corepressor.…”