title: MicroRNA-326 regulates profibrotic functions of transforming growth factor-β in pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal disorder resulting from the progressive remodeling of lungs, with no known effective treatment. Although transforming growth factor (TGF)-β has a well-established role in lung fibrosis, clinical experience with neutralizing antibodies to TGF-β has been disappointing, and strategies to directly suppress TGF-β1 secretion are needed. In this study we used a combination of in silico, in vitro, and in vivo approaches to identify microRNAs involved in TGF-β1 regulation and to validate the role of miR-326 in pulmonary fibrosis.We show that hsa-miR-326 regulates TGF-β1 expression and that hsa-miR-326 levels are inversely correlated to TGF-β1 protein levels in multiple human cell lines. The increase in TGF-β1 expression during the progression of bleomycin-induced lung fibrosis in mice was associated with loss of mmu-miR-326. Restoration of mmu-miR-326 levels by intranasal delivery of miR-326 mimics was sufficient to inhibit TGF-β1 expression and attenuate the fibrotic response. Moreover, human IPF lung specimens had markedly diminished miR-326 expression as compared with nonfibrotic lungs. Additional targets of miR-326 controlling TGF-β signaling and fibrosis-related pathways were identified, and miR-326 was found to down-regulate profibrotic genes, such as Ets1, Smad3, and matrix metalloproteinase 9, whereas it up-regulates antifibrotic genes, such as Smad7. Our results suggest for the first time that miR-326 plays a key role in regulating TGF-β1 expression and other profibrotic genes and could be useful in developing better therapeutic strategies for alleviating lung fibrosis.
authors.affiliation: 1 Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung Disease, CSIR-Institute of Genomics and Integrative Biology, Delhi, India; and.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Das
authors.forename: Manish
authors.initials: M
authors.lastname: Kumar
authors.forename: Vinny
authors.initials: V
authors.lastname: Negi
authors.forename: Bijay
authors.initials: B
authors.lastname: Pattnaik
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
authors.forename: Anurag
authors.initials: A
authors.lastname: Agrawal
authors.forename: Balaram
authors.initials: B
authors.lastname: Ghosh
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C545322:MIRN326 microRNA, human; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1