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* Division of Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, MD 21224;
Dartmouth Medical School, Lebanon, NH 03755;
Department of Surgery and Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212; and
Laboratory of Cellular and Molecular Biology, National Institute of Aging, National Institutes of Health, Baltimore, MD 21224
Glucocorticoids (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-
was similarly affected, as was the antagonistic effect of GC on TNF--induced response. Inflammatory genes, including cytokines 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant R01 AI060990-01A1 (to C.S.). F.T.I. was the recipient of the 2007 Strategic Training in Allergy Research (ST*AR) Award from the American Academy of Allergy, Asthma, and Immunology. M.G. was supported by the National Institute on Aging–Intramural Research Program, National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Cristiana Stellato, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Room 1A.12A, Baltimore, MD 21224. E-mail address: stellato{at}jhmi.edu
3 Abbreviations used in this paper: GC, glucocorticoid; GR, GC receptor; ARE, adenylate/uridylate-rich region; UTR, untranslated region; KO, knockout; TTP, tristetraprolin; RBP, RNA-binding protein; INOS, inducible NO synthase; MEF, mouse embryonic fibroblast; PBEC, primary bronchial epithelial cell; WT, wild type; Act D, actinomycin D; IP, immunoprecipitation; CT, cycle threshold; GO, gene ontology; RNP, ribonucleoprotein; mRNP, messenger RNP; RNAi, RNA interference; PCA, principal component analysis; Egr-1, early growth response-1; PTR, posttranscriptional regulation; siRNA, small interfering RNA.
4 The online version of this article contains supplemental material.
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