Repression of TNF-α-induced IL-8 expression by the glucocorticoid receptor-β involves inhibition of histone H4 acetylation

Sang-Hoon Kim,Paul Lavender,Sahng-June Kwak,Yun-Seop Kim,Young-Koo Jee,Ji-Hee Seo,Doh-Hyung Kim,Jae-Suk Park

doi:10.3858/emm.2009.41.5.033

Abstract

Increased expression of a number of proinflammatory genes, including IL-8, is associated with inflammatory conditions such as asthma. Glucocorticoid receptor (GR)beta, one of the GR isoforms, has been suggested to be upregulated in asthma associated with glucocorticoid insensitivity and to work as a dominant negative inhibitor of wild type GRalpha. However, recent data suggest that GRbeta is not a dominant negative inhibitor of GRalpha in the transrepressive process and has its own functional role. We investigated the functional role of GRbeta expression in the suppressive effect of glucocorticoids on tumor necrosis factor (TNF)-alpha-induced IL-8 release in an airway epithelial cell line. GRbeta expression was induced by treatment of epithelial cells with either dexamethasone or TNF-alpha. GRbeta was able to inhibit glucocorticoid-induced transcriptional activation mediated by binding to glucocorticoid response elements (GREs). The suppressive effect of dexamethasone on TNF-alpha-induced IL-8 transcription was not affected by GRbeta overexpression, rather GRbeta had its own weak suppressive activity on TNF-alpha-induced IL-8 expression. Overall histone deacetylase activity and histone acetyltransferase activity were not changed by GRbeta overexpression, but TNF-alpha-induced histone H4 acetylation at the IL-8 promoter was decreased with GRbeta overexpression. This study suggests that GRbeta overexpression does not affect glucocorticoid-induced suppression of IL-8 expression in airway epithelial cells and GRbeta induces its own histone deacetylase activity around IL-8 promoter site.

Highlights

Glucocorticoids are the mainstay of treatment of various inflammatory diseases such as bronchial asthma (Bateman et al, 2008)
GRβ overexpression affected neither the tumor necrosis factor (TNF)-α-induced IL-8 expression nor the suppression of IL-8 expression by dexamethasone, rather it looked like that GRβ had its own weak activity suppressing TNF-α induced IL-8 expression
We demonstrated that GRβ overexpression was able to reduce the degree of histone acetylation detected in the IL-8 promoter region following stimulation by TNF-α

Summary

Introduction

Glucocorticoids are the mainstay of treatment of various inflammatory diseases such as bronchial asthma (Bateman et al, 2008). Glucocorticoids work through the glucocorticoid receptor (GR), and transcriptional activation by GR is often mediated by GR binding to a consensus glucocorticoid response element (GRE). GR forms homodimers upon binding of glucocorticoid, and this homodimer binds to the GRE enabling recruitment of transcriptional co-activators. It has been described that multiple isoforms of GR are generated from a single gene by the mechanisms of alternative splicing and alternative translation initiation (Duma et al, 2006). Of these isoforms, two (GRα and GRβ) have been best studied, and they originate by an alternative splicing event within the 9th exon of the gene. GRβ was more highly expressed in glucocorticoid resistant asthmatics (Leung et al, 1997; Hamid et al, 1999; Sousa et al, 2000), this is not a universal observation in glucocorticoid dependent

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