title: MicroRNA-let-7a expression is increased in the mesangial cells of NZB/W mice and increases IL-6 production in vitro.
abstract: Recent evidence supports a role for epigenetic alterations in the pathogenesis of systemic lupus erythematosus (SLE). MicroRNAs (miRNAs or miRs) are endogenous epigenetic regulators whose expression is altered in many diseases, including SLE. IL-6 is an inflammatory cytokine produced by mesangial cells during lupus nephritis (LN). IL-6 contains a potential binding site for miRNA-let-7a (let-7a) in its 3' untranslated region (UTR). We found let-7a expression was significantly increased in the mesangial cells of pre-diseased and actively diseased New Zealand Black/White (NZB/W) mice compared to age-matched New Zealand White (NZW) mice. Overexpression of let-7a in vitro increased IL-6 production in stimulated mesangial cells compared to non-transfected controls. Inhibition of let-7a did not significantly affect immune-stimulated IL-6 production. When stimulated mesangial cells overexpressing let-7a were treated with the transcription inhibitor Actinomycin D (ActD), IL-6 was degraded faster, consistent with the direct targeting of the 3' UTR of IL-6 by let-7a. Overexpression of let-7a increased the expression of tristetraprolin (TTP), an RNA-binding protein (RBP) that has 5 potential binding regions in the 3' UTR of IL-6. ActD inhibited the transcription of proteins including TTP that may contribute to the let-7a-mediated increase in immune-stimulated IL-6 production. These data show that NZB/W mice have higher let-7a expression than NZW mice and that increased let-7a expression in vitro increases IL-6 production in stimulated mesangial cells. Further studies examining the role of let-7a expression in inflammation are warranted.
authors.affiliation: Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. cchafin@vt.edu
authors.forename: Cristen B
authors.initials: CB
authors.lastname: Chafin
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Regna
authors.forename: Rujuan
authors.initials: R
authors.lastname: Dai
authors.forename: David L
authors.initials: DL
authors.lastname: Caudell
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Reilly
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D015850:Interleukin-6; D008070:Lipopolysaccharides; D035683:MicroRNAs; D051816:Tristetraprolin; C542687:mirnlet7 microRNA, mouse; D007371:Interferon-gamma