Suppressive oligodeoxynucleotides inhibit atherosclerosis in ApoE(-/-) mice through modulation of Th1/Th2 balance.

Abstract

Atherosclerosis is a chronic inflammatory disease, which is positively and negatively regulated by T helper (Th) 1 and Th2 lymphocytes, respectively. Recent findings indicate that suppressive oligodeoxynucleotides (ODNs) expressing TTAGGG motifs selectively reduce Th1 cytokine production and have been proven effective at blocking the development of organ-specific autoimmune diseases. In the current research, we hypothesized that suppressive ODNs may alter the development of atherosclerosis. Eight-week-old homozygous ApoE(-/-) male mice were injected with 300 mug ODNs A151 (TTAGGG) or nonspecific ODNs 1612. Atherosclerotic lesion sizes were dramatically reduced by ODNs A151, but not by nonspecific ODNs. MCP-1 and VCAM-1, which are the key inflammatory factors in atherogenesis, were significantly attenuated by the suppressive ODNs A151. In the splenic lymphocytes, FACS analysis showed ODNs A151 reduced the percentage of IFN-gamma-producing Th1 cells and slightly increased the percentage of IL-4-producing Th2 cells, indicating that suppressive ODNs skewed the Th1/Th2 balance toward Th2 inflammation in vivo. Furthermore, ODNs A151 down-regulated the phosphorylation of STAT1 and STAT4 and suppressed up-regulation of T-bet, a signal modulator for Th1, and didn't impact GATA-3 and STAT6, which are associated with a Th2 phenotype. Consistent with this in vivo observation, ELISA analysis demonstrated that ODNs A151 suppressed Th1 cytokines IFN-gamma and TNF-alpha, and augmented Th2 cytokines IL-4 and IL-10 in vitro. This study provides the first experimental evidence that suppressive ODNs inhibit the development of atherosclerosis through inhibition of the STAT1/4 and T-bet pathways, which further modulate the Th1/Th2 balance in vivo.

• Authors: Xiang Cheng, Yong Chen, Jiang-Jiao Xie, Rui Yao, Xian Yu, Meng-Yang Liao, Ying-Jun Ding, Ting-Ting Tang, Yu-Hua Liao, Yan Cheng
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 45 Issue 2 Pg. 168-75 (Aug 2008) ISSN: 1095-8584 [Electronic] England
• PMID: 18502445 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• CPG-oligonucleotide
• Immunosuppressive Agents
• Oligodeoxyribonucleotides

Topics

• Animals
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (genetics, immunology, prevention & control, therapy)
• Cells, Cultured
• CpG Islands (immunology)
• Immunosuppressive Agents (administration & dosage)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Oligodeoxyribonucleotides (administration & dosage)
• Signal Transduction (genetics, immunology)
• Th1 Cells (drug effects, immunology)
• Th2 Cells (drug effects, immunology)