title: Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality.
abstract: While miRNAs are increasingly linked to various immune responses, whether they can be targeted for regulating in vivo inflammatory processes such as endotoxin-induced Gram-negative sepsis is not known. Production of cytokines by the dendritic cells (DCs) plays a critical role in response to endotoxin, lipopolysaccharide (LPS). We profiled the miRNA and mRNA of CD11c⁺ DCs in an unbiased manner and found that at baseline, miR-142-3p was among the most highly expressed endogenous miRs while IL-6 was among the most highly expressed mRNA after LPS stimulation. Multiple computational algorithms predicted the IL-6 3' untranslated region (UTR) to be a target of miR-142-3p. Studies using luciferase reporters carrying wild-type (WT) and mutant IL-6 3'UTR confirmed IL-6 as a target for miR-142-3p. In vitro knockdown and overexpression studies demonstrated a critical and specific role for miR142-3p in regulating IL-6 production by the DCs after LPS stimulation. Importantly, treatment of only WT but not the IL-6-deficient (IL-6(⁻/⁻)) mice with locked nucleic acid (LNA)-modified phosphorothioate oligonucleotide complementary to miR 142-3p reduced endotoxin-induced mortality. These results demonstrate a critical role for miR-142-3p in regulating DC responses to LPS and provide proof of concept for targeting miRs as a novel strategy for treatment of endotoxin-induced mortality.
authors.affiliation: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Maher
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.forename: Peter
authors.initials: P
authors.lastname: Chockley
authors.forename: Tomomi
authors.initials: T
authors.lastname: Toubai
authors.forename: Chelsea
authors.initials: C
authors.lastname: Malter
authors.forename: Evelyn
authors.initials: E
authors.lastname: Nieves
authors.forename: Isao
authors.initials: I
authors.lastname: Tawara
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Wang
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
authors.forename: Arul
authors.initials: A
authors.lastname: Chinnaiyan
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D039521:CD11c Antigen / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D018805:Sepsis / Q000139:chemically induced / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D039521:CD11c Antigen; D015850:Interleukin-6; D008070:Lipopolysaccharides; D035683:MicroRNAs; C529102:Mirn142 microRNA, mouse