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Molecular and Cellular Biology, December 2006, p. 9126-9135, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.00679-06

Glucocorticoids Regulate Tristetraprolin Synthesis and Posttranscriptionally Regulate Tumor Necrosis Factor Alpha Inflammatory Signaling{triangledown}

Kathleen Smoak and John A. Cidlowski*

Laboratory of Signal Transduction, National Institute of Environmental Health Services, National Institutes of Health, Department of Health and Human Services, Building 101, Research Triangle Park, North Carolina 27709

Received 19 April 2006/ Returned for modification 17 May 2006/ Accepted 6 September 2006

Glucocorticoids are used to treat various inflammatory disorders, but the mechanisms underlying these actions are incompletely understood. The zinc finger protein tristetraprolin (TTP) destabilizes several proinflammatory cytokine mRNAs by binding to AU-rich elements within their 3' untranslated regions, targeting them for degradation. Here we report that glucocorticoids induce the synthesis of TTP mRNA and protein in A549 lung epithelial cells and in rat tissues. Dexamethasone treatment leads to a sustained induction of TTP mRNA expression that is abrogated by RU486. Glucocorticoid induction of TTP mRNA is also blocked by actinomycin D but not by cycloheximide, suggesting a transcriptional mechanism which has been confirmed by transcription run-on experiments. The most widely characterized TTP-regulated gene is the AU-rich tumor necrosis factor alpha (TNF-{alpha}) gene. Dexamethasone represses TNF-{alpha} mRNA in A549 cells and decreases luciferase expression of a TNF-{alpha} 3' untranslated region reporter plasmid in an orientation-dependent manner. Small interfering RNAs to TTP significantly prevent this effect, and a cell line stably expressing a short-hairpin RNA to TTP conclusively establishes that TTP is critical for dexamethasone inhibition of TNF-{alpha} mRNA expression. These studies provide the molecular evidence for glucocorticoid regulation of human TTP and reflect a novel inductive anti-inflammatory signaling pathway for glucocorticoids that acts via posttranscriptional mechanisms.

* Corresponding author. Mailing address: Department of Health and Human Services, Laboratory of Signal Transduction, National Institute of Environmental Health Services, National Institutes of Health, Building 101, Research Triangle Park, NC 27709. Phone: (919) 541-1564. Fax: (919) 541-1367. E-mail: cidlowski{at}niehs.nih.gov.

{triangledown} Published ahead of print on 18 September 2006.

Molecular and Cellular Biology, December 2006, p. 9126-9135, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.00679-06




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