A Dual AP-1 and SMAD Decoy ODN Suppresses Tissue Fibrosis and Scarring in Mice

• DOI: 10.1038/jid.2012.443
• Publication Date: 2012-12-06T09:29:23Z
• Authors: Hong-Feng Yuan; Hong Huang; Xiang-Yun Li; Wei Guo; Wei Xing; Zhi-Ya Sun; Hua-Ping Liang; Jian Yu; Dong-Feng Chen; Zheng-Guo Wang; Jin Hao; Xiang Xu
• Keywords: Male; Transcriptional Activation; Apoptosis; Smad Proteins; Dermatology; Biochemistry; Cicatrix; Mice; 03 medical and health sciences; Genes, Reporter; Animals; Molecular Biology; Cell Proliferation; Mice, Inbred BALB C; 0303 health sciences; Cell Biology; Dermis; Genetic Therapy; Fibrosis; Transcription Factor AP-1; Disease Models, Animal; Oligodeoxyribonucleotides; Drug Design; Acute Disease; NIH 3T3 Cells; Signal Transduction

The transforming growth factor-β (TGF-β) signaling pathway promotes tissue fibrosis and scarring through SMAD (small mothers against decapentaplegic)-dependent and SMAD-independent mechanisms. However, inhibition of SMAD-mediated signal transduction alone induces an excessive inflammatory response that impairs the antifibrotic effects of TGF-β inhibitors. In this study, we designed and characterized a dual-functional transcription activator protein 1 (AP-1) and SMAD decoy oligodeoxynucleotide, antifibrosis oligodeoxynucleotide 4 (AFODN4) in vitro and in vivo. AFODN4 binds directly to recombinant AP-1 and SMAD with high affinity. AFODN4 significantly inhibited the DNA-binding and transcriptional activities of both AP-1 and SMAD, as well as the production of fibrotic mediators stimulated by TGF-β1 or TGF-β2 in L929 murine fibroblasts. Local administration of AFODN4 significantly inhibited fibrosis associated with acute dermal wounds in mice. Intriguingly, AFODN4 inhibited AP-1-mediated production of proinflammatory mediators, which can be caused by blockage of SMAD alone in vitro and in vivo. Collectively, these findings suggest that dual inhibition of SMAD and AP-1 signaling by AFODN4 is a useful strategy for the development of new antifibrotic agents.