title: Proinflammatory role for let-7 microRNAS in experimental asthma.
abstract: MicroRNAs (miRNAs) are short, non-coding RNAs that target and silence protein coding genes through 3'-UTR elements. Evidence increasingly assigns an immunosuppressive role for miRNAs in immunity, but relatively few miRNAs have been studied, and an overall understanding of the importance of these regulatory transcripts in complex in vivo systems is lacking. Here we have applied multiple technologies to globally analyze miRNA expression and function in allergic lung disease, an experimental model of asthma. Deep sequencing and microarray analyses of the mouse lung short RNAome revealed numerous extant and novel miRNAs and other transcript classes. Similar to mRNAs, lung miRNA expression changed dynamically during the transition from the naive to the allergic state, suggesting numerous functional relationships. A possible role for miRNA editing in altering the lung mRNA target repertoire was also identified. Multiple members of the highly conserved let-7 miRNA family were the most abundant lung miRNAs, and we confirmed in vitro that interleukin 13 (IL-13), a cytokine essential for expression for allergic lung disease, is regulated by mmu-let-7a. However, inhibition of let-7 miRNAs in vivo using a locked nucleic acid profoundly inhibited production of allergic cytokines and the disease phenotype. Our findings thus reveal unexpected complexity in the miRNAome underlying allergic lung disease and demonstrate a proinflammatory role for let-7 miRNAs.
authors.affiliation: From the Department of Medicine.
authors.forename: Sumanth
authors.initials: S
authors.lastname: Polikepahad
authors.forename: John M
authors.initials: JM
authors.lastname: Knight
authors.forename: Arash O
authors.initials: AO
authors.lastname: Naghavi
authors.forename: Toni
authors.initials: T
authors.lastname: Oplt
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Chad
authors.initials: C
authors.lastname: Shaw
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Benham
authors.forename: Jong
authors.initials: J
authors.lastname: Kim
authors.forename: Benjamin
authors.initials: B
authors.lastname: Soibam
authors.forename: R Alan
authors.initials: RA
authors.lastname: Harris
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.forename: Azam
authors.initials: A
authors.lastname: Zariff
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Milosavljevic
authors.forename: Lakeisha M
authors.initials: LM
authors.lastname: Batts
authors.forename: Farrah
authors.initials: F
authors.lastname: Kheradmand
authors.forename: Preethi H
authors.initials: PH
authors.lastname: Gunaratne
authors.forename: David B
authors.initials: DB
authors.lastname: Corry
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018793:Interleukin-13 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*
chemical_list: D018793:Interleukin-13; D035683:MicroRNAs; C542687:mirnlet7 microRNA, mouse