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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
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NF-kappaB-dependent regulation of tumor necrosis factor-alpha gene expression by CpG-oligodeoxynucleotides

Hyung-Joo Kwon1, Keun-Wook Lee, Sang Ho Yu

  • 1Institute of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.

Biochemical and Biophysical Research Communications
|October 25, 2003
PubMed

Insights

Synthetic CpG oligodeoxynucleotides (CpG-ODNs) can be potent immunotherapeutics. Modifying their sequences and backbones can optimize immune responses and reduce harmful side effects.

Area of Science:

  • Immunology
  • Molecular Biology
  • Drug Discovery

Background:

  • Synthetic oligodeoxynucleotides (CpG-ODNs) are investigated for their immunostimulatory properties and potential as immunotherapeutics.
  • CpG-ODNs can induce potent immune responses, including the production of tumor necrosis factor-alpha (TNF-alpha), which can lead to harmful shock effects.

Purpose of the Study:

  • To investigate the impact of phosphorothioate backbone modification and sequence variations on the immunostimulatory activity of CpG-ODNs.
  • To identify key molecular pathways involved in CpG-ODN-mediated activation of the innate immune response.

Main Methods:

  • Comparison of TNF-alpha gene expression, promoter activity, IkappaB degradation, and NF-kappaB activation between phosphorothioate-modified oligodeoxynucleotides (PS-ODNs) and phosphodiester ODN (PO-ODN) for CpG-ODN 1826 and CpG-ODN 2006.
  • Transient transfection assays to determine the role of myeloid differentiation protein (MyD88) and tumor necrosis factor receptor-associated factor 6 (TRAF6) in CpG-ODN-induced TNF-alpha promoter activation.

Main Results:

  • PS-ODN of CpG-ODN 1826 demonstrated significantly higher stimulatory activity compared to its PO-ODN counterpart.
  • Conversely, PS-ODN of CpG-ODN 2006 exhibited lower stimulatory activity than its PO-ODN.
  • MyD88 and TRAF6 were identified as common essential factors for TNF-alpha promoter activation by various CpG-ODNs.

Conclusions:

  • The potency of CpG-ODNs can be modulated through sequence rearrangement and phosphorothioate backbone modification.
  • These modifications offer a strategy to optimize innate immune responses while potentially mitigating adverse effects.
  • Understanding the roles of MyD88 and TRAF6 provides insights into the mechanisms of CpG-ODN action.

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