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Mol Endocrinol. 2009 Jan;23(1):86-99. doi: 10.1210/me.2008-0257. Epub 2008 Oct 22.

A novel mitogen-activated protein kinase phosphatase-1 and glucocorticoid receptor (GR) interacting protein-1-dependent combinatorial mechanism of gene transrepression by GR.

Author information

1
Innovative Drug Research Center for Metabolic and Inflammatory Disease, College of Pharmacy, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, Korea.

Abstract

Glucocorticoids have major antiinflammatory effects. Because COX-2 is the rate-limiting enzyme for proinflammatory prostaglandins, this study investigated the combinatorial inhibitory role of glucocorticoid receptor (GR) in COX-2 gene induction in macrophages and sought to identify the molecular mechanisms for that inhibition. Glucocorticoid-activated GR repressed COX-2 gene induction by lipopolysaccharide (LPS). Activated GR inhibited LPS-induced activator protein 1 activity, which in turn decreased activating transcription factor 2/c-Jun phosphorylation. The inhibition of MAPK-dependent activating transcription factor 2/c-Jun phosphorylation by GR in COX-2 repression was a result of MAPK phosphatase-1 (MKP-1) induction. Although GR did not inhibit LPS-induced p65 phosphorylation or nuclear factor-kappaB DNA binding activity, deletion of the nuclear factor-kappaB binding site in the COX-2 gene suppressed the ability of glucocorticoid to attenuate COX-2 induction. Chromatin immunoprecipitation and transfection assays revealed that a p65 DNA complex involving GR-bound GR-interacting protein 1 (GRIP1) also contributed to COX-2 repression. Additional knockdown and transfection assays identified other inflammatory genes coordinately regulated by MKP-1 and GRIP1. In summary, activated GR was found to antagonize the LPS-dependent induction of the COX-2 gene via a novel combinatorial mechanism involving MKP-1-mediated activator protein 1 inhibition and GR/GRIP1 recruitment to the p65 DNA complex; moreover, this work facilitated the identification of other GR-responding MKP-1/GRIP1-regulated genes.

PMID:
18945810
PMCID:
PMC5419322
DOI:
10.1210/me.2008-0257
[Indexed for MEDLINE]
Free PMC Article

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