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.
Highlights
Toll-like receptors (TLRs) recognize a set of conserved molecular structures called pathogenassociated molecular patterns, which allow them to sense innate and adaptive immune responses
The present study investigated the role of FoxO3a transcription factor in Toll-like receptor 9 (TLR9)-mediated anti-apoptosis of macrophages
Apoptosis was examined in TLR9 stimulated and non-stimulated Raw264.7 cells in response to serum deprivation by evaluating the percentage of propidium iodide (PI) or annexin-V stained cells
Summary
Toll-like receptors (TLRs) recognize a set of conserved molecular structures called pathogenassociated molecular patterns, which allow them to sense innate and adaptive immune responses. After CpG DNA binding, TLR9 signaling is initiated by recruitment of the adaptor molecule MyD88 followed by the engagement of interleukin (IL)-1R-associated kinases and tumor necrosis factor (TNF)-α receptor (TNFR)-associated factor 6 (Kawai et al, 2004). These complexes can activate the IκB kinase complex and subsequently activate NFκB-dependent pro-inflammatory cytokines such as TNF-α and IL-1β (Bagchi et al, 2007). TLRs are members of the IL-1R superfamily and share a common activation pathway by their Toll/IL-1R signaling domain (Boraschi and Tagliabue, 2006) Despite this common pathway, TLRs show differences in their rate, intensity, or efficiency of activation by as yet unidentified mechanisms. Selective pathways are triggered by some TLRs; in particular, TLR2, TLR4, and TLR9 can activate the phosphatidylinositol 3 kinase (PI3K) pathway (Francois et al, 2005)
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