title: 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.affiliation: Department of Blood Transfusion, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Yue-Hui
authors.initials: YH
authors.lastname: Liu
authors.forename: Sha-Ling
authors.initials: SL
authors.lastname: Li
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Fu
authors.forename: Rong-Rong
authors.initials: RR
authors.lastname: Zhou
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Xue-Gong
authors.initials: XG
authors.lastname: Fan
mesh_terms: D000818:Animals; D001483:Base Sequence; D005260:Female; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D059372:Nucleotide Motifs; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D010766:Phosphorylation; D050797:STAT4 Transcription Factor / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D009838:Oligodeoxyribonucleotides; D050797:STAT4 Transcription Factor; D015847:Interleukin-4; D007371:Interferon-gamma