title: p53 regulates Toll-like receptor 3 expression and function in human epithelial cell lines.
abstract: 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 IkappaB-alpha, nuclear translocation of NF-kappaB, 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.
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Taura
authors.forename: Ayaka
authors.initials: A
authors.lastname: Eguma
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Suico
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shuto
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.forename: Kensei
authors.initials: K
authors.lastname: Komatsu
authors.forename: Takefumi
authors.initials: T
authors.lastname: Komune
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D051196:Toll-Like Receptor 3; D016159:Tumor Suppressor Protein p53; D011070:Poly I-C
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