Protective role of synthetic oligodeoxynucleotides expressing immunosuppressive TTAGGG motifs in concanavalin A-induced hepatitis.

Abstract

Synthetic suppressive oligodeoxynucleotides (ODNs) expressing TTAGGG motifs selectively reduce Th1 cytokine production and have been proven effective in T helper type 1 (Th1)-mediated autoimmune diseases. Concanavalin A (Con A)-induced hepatitis is characterized by elevated Th1 response. The present study aims to reveal a profound hepatoprotective effect of suppressive ODNs on Con A-induced hepatitis. BALB/c mice were injected with suppressive ODNs (i) prior to, (ii) simultaneously with, or (iii) after Con A challenge. The effect of suppressive ODNs on interferon (IFN)-γ and interleukin (IL)-4 expressions was determined. The effect of suppressive ODNs on signal modulators for Th1/Th2 pathway was examined. Our results showed that suppressive ODNs significantly reduced liver necroinflammatory injury and serum IFN-γ level, meanwhile increased IL-4 level. The mortality of suppressive ODNs-treated mice was reduced from 30% to 0% in 8h post Con A challenge. In the splenic lymphocytes, Western blot analysis showed that suppressive ODNs down-regulated the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT4, and suppressed up-regulation of T-bet, but did not impact the phosphorylation of STAT6 which are associated with a Th2 phenotype. Consistent with this in vivo observation, ELISA analysis demonstrated that suppressive ODNs inhibited IFN-γ, and augmented IL-4 production in the differentiation of naive T cells in vitro. We concluded that suppressive ODNs inhibit the development of Con A-induced hepatitis through down-regulation of the STAT1/4 and T-bet pathways and may be of use in the treatment of autoimmune or viral hepatitis in humans.

• Authors: Ning Li, Yue-Hui Liu, Sha-Ling Li, Chun-Yan Fu, Rong-Rong Zhou, Yan Huang, Xue-Gong Fan
• Journal: Immunology letters (Immunol Lett) Vol. 151 Issue 1-2 Pg. 54-60 (Mar 2013) ISSN: 1879-0542 [Electronic] Netherlands
• PMID: 23470496 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Immunosuppressive Agents
• Oligodeoxyribonucleotides
• STAT4 Transcription Factor
• Interleukin-4
• Interferon-gamma

Topics

• Animals
• Base Sequence
• Female
• Hepatitis, Animal (chemically induced, immunology, prevention & control)
• Immunosuppressive Agents (administration & dosage, chemistry, immunology)
• Interferon-gamma (biosynthesis)
• Interleukin-4 (biosynthesis)
• Mice
• Nucleotide Motifs
• Oligodeoxyribonucleotides (administration & dosage, chemistry, immunology)
• Phosphorylation
• STAT4 Transcription Factor (metabolism)
• T-Lymphocyte Subsets (immunology, metabolism)