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Molecular and Cellular Biology, November 2008, p. 6557-6567, Vol. 28, No. 21
0270-7306/08/$08.00+0     doi:10.1128/MCB.01202-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

p53 Regulates Toll-Like Receptor 3 Expression and Function in Human Epithelial Cell Lines{triangledown}

Manabu Taura,1 Ayaka Eguma,1 Mary Ann Suico,1 Tsuyoshi Shuto,1 Tomoaki Koga,1 Kensei Komatsu,1 Takefumi Komune,1 Takashi Sato,1 Hideyuki Saya,2 Jian-Dong Li,3 and Hirofumi Kai1*

Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan,1 Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan,2 Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 146423

Received 31 July 2008/ Returned for modification 27 August 2008/ Accepted 29 August 2008

Toll-like receptors (TLRs) are important sensors of microbial pathogens and mediators of innate immune responses. Although the signal transduction of TLRs is well elucidated, their basal regulation is largely unexplored. Here we show that the tumor suppressor p53 positively regulates the transcription of TLR3, a receptor for viral double-stranded RNA and poly(I-C), by binding to the p53 site in the TLR3 promoter. TLR3 expression was lower in HCT116 p53–/– cells than in HCT116 p53+/+ cells. Activation of p53 by 5-fluorouracil increased the TLR3 mRNA in epithelial cell lines with wild-type p53 but not in cell lines harboring mutant p53. Knockdown of p53 by small interfering RNA decreased the TLR3 expression. TLR3 mRNA was also lower in liver and intestine of p53–/– mice than in p53+/+ mice. Furthermore, the poly(I-C)-induced phosphorylation of I{kappa}B-{alpha}, nuclear translocation of NF-{kappa}B, and phosphorylation of interferon regulatory transcription factor 3, were drastically reduced in HCT116 p53–/– cells, indicating a dysregulation of the two signaling pathways governed by TLR3. Consequently, induction of interleukin-8 and beta interferon after poly(I-C) stimulation was impaired in HCT116 p53–/– cells. These results suggest that p53 influences TLR3 expression and function and highlight a role of p53 in innate immune response in epithelial cells.

* Corresponding author. Mailing address: 5-1 Oe-honmachi, Kumamoto 862-0973, Japan. Phone and fax: 81-96-371-4405. E-mail: hirokai{at}gpo.kumamoto-u.ac.jp

{triangledown} Published ahead of print on 8 September 2008.

Molecular and Cellular Biology, November 2008, p. 6557-6567, Vol. 28, No. 21
0270-7306/08/$08.00+0     doi:10.1128/MCB.01202-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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