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

Eun-Jung Lim1, Dae-Weon Park, Tae-Whal Jeong

  • 1Department of Biochemistry and Molecular Biology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea.

Oncology Reports
|December 14, 2011
PubMed

Insights

Synthetic CpG oligodeoxynucleotides (ODNs) trigger toll-like receptor 9 (TLR9) signaling. CpG ODNs reduce tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and apoptosis via the Akt-FoxO3a pathway.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Synthetic oligodeoxynucleotides (ODNs) containing CpG motifs activate toll-like receptor 9 (TLR9), initiating immune responses.
  • Serum starvation of Raw264.7 cells enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression.
  • CpG ODN treatment was observed to decrease TRAIL expression and apoptosis induced by serum starvation.

Purpose of the Study:

  • To investigate the mechanism by which CpG ODN downregulates TRAIL expression and affects apoptosis in serum-starved cells.
  • To elucidate the role of the Akt-FoxO3a signaling pathway in TLR9-mediated cellular responses.

Main Methods:

  • Utilized Raw264.7 cells subjected to serum starvation and treated with CpG ODN.
  • Employed TLR9 inhibitors, small interfering RNA (siRNA) for FoxO3a knockdown, and specific inhibitors (LY294002) and overexpression of Akt.
  • Assessed TRAIL expression, apoptosis (sub-G1 accumulation), and signaling pathway activation (Akt, FoxO3a).

Main Results:

  • CpG ODN treatment reduced TRAIL expression and apoptosis in serum-starved cells.
  • TLR9 inhibitors reversed the effects of CpG ODN, restoring TRAIL expression and apoptosis.
  • CpG ODNs activated Akt and inactivated FoxO3a, a process crucial for the observed anti-apoptotic effects, as confirmed by siRNA knockdown and overexpression studies.
  • Inhibition of PI3K-Akt pathway blocked CpG ODN's effects on TRAIL and apoptosis.

Conclusions:

  • The Akt-FoxO3a signaling pathway is a key mediator of TLR9-induced downregulation of TRAIL expression.
  • CpG ODNs exert anti-apoptotic effects in serum-starved cells through the modulation of the Akt-FoxO3a pathway.
  • These findings highlight a novel mechanism linking innate immune receptor signaling to apoptosis regulation.

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