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

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.