TRAIL is involved in CpG ODN-mediated anti-apoptotic signals

Synthetic oligodeoxynucleotides (ODNs) with the CpG-motifs are recognizedby toll-like receptor 9 (TLR9), which elicits an immune response. Serum starvationof Raw264.7 cells increased tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) expression. However, treatment with CpG ODN reduced TRAIL expression aswell as apoptosis by serum starvation. In serum starved cells, TLR9 inhibitorsrecovered the decreasing TRAIL expression and sub-G1 accumulation by CpG ODN.CpG ODN-regulated anti-apoptotic signals which were dependent on the Akt-FoxO3asignaling pathway. CpG ODNs activated Akt and inactivated FoxO3a in serum starvedcells. Knockdown of FoxO3a by siRNA decreased TRAIL expression and apoptosis inserum-starved cells. In contrast, FoxO3a overexpression increased apoptosis byserum starvation, and CpG ODNs blocked these effects through TRAIL expression.LY294002, a PI3K-Akt inhibitor, blocked the CpG ODN effect of TRAIL expressionand the sub-G1 population in serum starved cells. In contrast, overexpressionof wild-type Akt reduced additional sub-G1 cells both in non-CpG ODN- and CpGODN-treated cells. Taken together, these results demonstrate the involvement ofAkt-FoxO3a signaling in TLR9-mediated downregulation of TRAIL and anti-apoptoticsignals.