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Molecular and Cellular Biology, June 2004, p. 4743-4756, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.4743-4756.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Glucocorticoids and Tumor Necrosis Factor Alpha Cooperatively Regulate Toll-Like Receptor 2 Gene Expression

Marcela A. Hermoso,1 Tetsuya Matsuguchi,2 Kathleen Smoak,1 and John A. Cidlowski1*

Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709,1 Division of Biochemistry and Molecular Dentistry, Department of Developmental Medicine, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan2

Received 16 October 2003/ Returned for modification 13 November 2003/ Accepted 10 February 2004

Tumor necrosis factor alpha (TNF-{alpha}) and glucocorticoids are widely recognized as mutually antagonistic regulators of adaptive immunity and inflammation. Surprisingly, we show here that they cooperatively regulate components of innate immunity. The Toll-like receptor 2 (TLR2) gene encodes a transmembrane receptor critical for triggering innate immunity. Although TLR2 mRNA and protein are induced by inflammatory molecules such as TNF-{alpha}, we show that TLR2 is also induced by the anti-inflammatory glucocorticoids in cells where they also regulate MKP-1 mRNA and protein levels. TNF-{alpha} and glucocorticoids cooperate to regulate the TLR2 promoter, through the involvement of a 3' NF-{kappa}B site, a STAT-binding element, and a 3' glucocorticoid response element (GRE). Molecular studies show that the I{kappa}B{alpha} superrepressor or a STAT dominant negative element prevented TNF-{alpha} and dexamethasone stimulation of TLR2 promoter. Similarly, an AF-1 deletion mutant of glucocorticoid receptor or ablation of a putative GRE notably reduced the cooperative regulation of TLR2. Using chromatin immunoprecipitation assays, we demonstrate that all three transcription factors interact with both endogenous and transfected TLR2 promoters after stimulation by TNF-{alpha} and dexamethasone. Together, these studies define novel signaling mechanism for these three transcription factors, with a profound impact on discrimination of innate and adaptive immune responses.

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

Molecular and Cellular Biology, June 2004, p. 4743-4756, Vol. 24, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.11.4743-4756.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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