title: A dual AP-1 and SMAD decoy ODN suppresses tissue fibrosis and scarring in mice.
abstract: 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.
authors.affiliation: Third Military Medical University, Chongqing, China.
authors.forename: Hong-Feng
authors.initials: HF
authors.lastname: Yuan
authors.forename: Hong
authors.initials: H
authors.lastname: Huang
authors.forename: Xiang-Yun
authors.initials: XY
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Wei
authors.initials: W
authors.lastname: Xing
authors.forename: Zhi-Ya
authors.initials: ZY
authors.lastname: Sun
authors.forename: Hua-Ping
authors.initials: HP
authors.lastname: Liang
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.forename: Dong-Feng
authors.initials: DF
authors.lastname: Chen
authors.forename: Zheng-Guo
authors.initials: ZG
authors.lastname: Wang
authors.forename: Jin
authors.initials: J
authors.lastname: Hao
authors.forename: Xiang
authors.initials: X
authors.lastname: Xu
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D002921:Cicatrix / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D020405:Dermis / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015195:Drug Design; D005355:Fibrosis / Q000235:genetics / Q000473:pathology / Q000628:therapy; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology
chemical_list: D009838:Oligodeoxyribonucleotides; D051785:Smad Proteins; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta