Exp Mol Med.  2010 Oct;42(10):712-720. 10.3858/emm.2010.42.10.070.

Toll-like receptor 9-mediated inhibition of apoptosis occurs through suppression of FoxO3a activity and induction of FLIP expression

Affiliations
  • 1Aging-Associated Vascular Disease Research Center, Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu 705-802, Korea. sbaek@med.yu.ac.kr
  • 2Department of Biological Science, Sungkyunkwan University, Suwon 440-746, Korea.
  • 3Department of Dentistry, College of Medicine, Yeungnam University, Daegu 705-717, Korea.

Abstract

Synthetic oligodeoxynucleotides (ODN) with a CpG-motif are recognized by Toll-like receptor 9 (TLR9) and pleiotropic immune responses are elicited. Stimulation of macrophages with TLR9 agonist prevented apoptosis induced by serum deprivation through increased expression of FLICE-like inhibitory protein (FLIP). CpG ODN-mediated anti-apoptosis depended on the TLR9-Akt-FoxO3a signaling pathway. Inhibition of TLR9 by small interfering (si) RNA or an inhibitor suppressed CpG ODN-mediated anti-apoptosis. Analysis of signaling pathways revealed that the anti-apoptotic effect of CpG ODN required phosphorylation of FoxO3a and its translocation from the nucleus to the cytosol. Overexpression of FoxO3a increased apoptosis induced by serum deprivation and CpG ODN blocked these effects through FLIP expression. In contrast, siRNA knock-down of FoxO3a decreased apoptosis by serum deprivation. In addition, Akt activation was involved in CpG ODN-induced phosphorylation of FoxO3a, expression of FLIP, and anti-apoptosis. Taken together, these results demonstrate the involvement of Akt-FoxO3a in TLR9-mediated anti-apoptosis and indicate that FoxO3a is a distinct regulator for FLIP expression.

Keyword

Apoptosis; CpG ODN; FLIP; FoxO3a; Toll-like receptor 9

MeSH Terms

Animals
*Apoptosis
CASP8 and FADD-Like Apoptosis Regulating Protein/*genetics/metabolism
Cells, Cultured
Forkhead Transcription Factors/genetics/*metabolism
Macrophages/metabolism
Mice
Mice, Inbred C57BL
Oligodeoxyribonucleotides/metabolism
Oncogene Protein v-akt/metabolism
RNA, Small Interfering/metabolism
Signal Transduction
Toll-Like Receptor 9/genetics/*metabolism
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