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

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 prot...

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Published in:Experimental & molecular medicine 2010, 42(10), , pp.712-720
Main Authors: Lim, Eun-Jung, Park, Dae-Weon, Lee, Jin-Gu, Lee, Chu-Hee, Bae, Yoe-Sik, Hwang, Young-Chul, Jeong, Jae-Weon, Chin, Byung-Rho, Baek, Suk-Hwan
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biomedical and Life Sciences
Biomedicine
CASP8 and FADD-Like Apoptosis Regulating Protein - genetics
CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism
Cells, Cultured
Forkhead Box Protein O3
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - metabolism
Macrophages - metabolism
Medical Biochemistry
Mice
Mice, Inbred C57BL
Molecular Medicine
Oligodeoxyribonucleotides - metabolism
Oncogene Protein v-akt - metabolism
Original
RNA, Small Interfering - metabolism
Signal Transduction
Stem Cells
Toll-Like Receptor 9 - genetics
Toll-Like Receptor 9 - metabolism
생화학
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Summary: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.
ISSN:1226-3613
2092-6413
DOI:10.3858/emm.2010.42.10.070