Role of the RNA-binding protein tristetraprolin in glucocorticoid-mediated gene regulation

Faoud T. Ishmael, Xi Fang, Maria Rosaria Galdiero, UIus Atasoy, William F C Rigby, Myriam Gorospe, Chris Cheadle, Cristiana Stellato

Research output: Contribution to journalArticle

Abstract

Glucocorlicoids (GCs) are the mainstay of anti-inflammatory therapy. Modulation of posttranscriptional regulation (PTR) of gene expression by GCs is a relevant yet poorly characterized mechanism of their action. The RNA-binding protein tristetraprolin (TTP) plays a central role in PTR by binding to AU-rich elements in the 3′-untranslated region of proinflammatory transcripts and accelerating their decay. We found that GCs induce TTP expression in primary and immortalized human bronchial epithelial cells. To investigate the importance of PTR and the role of TTP in GC function, we compared the effect of GC treatment on genome-wide gene expression using mouse embryonic fibroblasts (MEFs) obtained from wild-type and TTP -/-mice. We confirmed that GCs induce TTP in MEFs and observed in TTP -/- MEFs a striking loss of up to 85% of GC-mediated gene expression. Gene regulation by TNF-α was similarly affected, as was the antagonistic effect of GC on TNF-a-induced response. Inflammatory genes, including cytokincs and chemokines, were among the genes whose sensitivity to GCs was affected by lack of TTP. Silencing of TTP in WT MEFs by small interfering RNA confirmed loss of GC response in selected targets. Immunoprecipitation of ribonucleoprotein complexes revealed binding of TTP to several validated transcripts. Changes in the rate of transcript degradation studied by actinomycin D were documented for only a subset of transcripts bound to TTP. These results reveal a strong and previously unrecognized contribution of PTR to the anti-inflammatory action of GCs and point at TTP as a key factor mediating this process through a complex mechanism of action.

Original languageEnglish (US)
Pages (from-to)8342-8353
Number of pages12
JournalJournal of Immunology
Volume180
Issue number12
StatePublished - 2008

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Tristetraprolin
RNA-Binding Proteins
Glucocorticoids
Genes
Fibroblasts
Anti-Inflammatory Agents
AU Rich Elements
Gene Expression
Ribonucleoproteins
Gene Expression Regulation
3' Untranslated Regions
Dactinomycin
Chemokines
Immunoprecipitation
Small Interfering RNA

ASJC Scopus subject areas

  • Immunology

Cite this

Ishmael, F. T., Fang, X., Galdiero, M. R., Atasoy, UI., Rigby, W. F. C., Gorospe, M., ... Stellato, C. (2008). Role of the RNA-binding protein tristetraprolin in glucocorticoid-mediated gene regulation. Journal of Immunology, 180(12), 8342-8353.

Role of the RNA-binding protein tristetraprolin in glucocorticoid-mediated gene regulation. / Ishmael, Faoud T.; Fang, Xi; Galdiero, Maria Rosaria; Atasoy, UIus; Rigby, William F C; Gorospe, Myriam; Cheadle, Chris; Stellato, Cristiana.

In: Journal of Immunology, Vol. 180, No. 12, 2008, p. 8342-8353.

Research output: Contribution to journalArticle

Ishmael, FT, Fang, X, Galdiero, MR, Atasoy, UI, Rigby, WFC, Gorospe, M, Cheadle, C & Stellato, C 2008, 'Role of the RNA-binding protein tristetraprolin in glucocorticoid-mediated gene regulation', Journal of Immunology, vol. 180, no. 12, pp. 8342-8353.
Ishmael FT, Fang X, Galdiero MR, Atasoy UI, Rigby WFC, Gorospe M et al. Role of the RNA-binding protein tristetraprolin in glucocorticoid-mediated gene regulation. Journal of Immunology. 2008;180(12):8342-8353.
Ishmael, Faoud T. ; Fang, Xi ; Galdiero, Maria Rosaria ; Atasoy, UIus ; Rigby, William F C ; Gorospe, Myriam ; Cheadle, Chris ; Stellato, Cristiana. / Role of the RNA-binding protein tristetraprolin in glucocorticoid-mediated gene regulation. In: Journal of Immunology. 2008 ; Vol. 180, No. 12. pp. 8342-8353.
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