Blood Journal
Leading the way in experimental and clinical research in hematology

Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality

  1. Yaping Sun1,
  2. Sooryanarayana Varambally2,
  3. Christopher A. Maher2,
  4. Qi Cao2,
  5. Peter Chockley1,
  6. Tomomi Toubai1,
  7. Chelsea Malter1,
  8. Evelyn Nieves1,
  9. Isao Tawara1,
  10. Yongqing Wang3,
  11. Peter A. Ward2,
  12. Arul Chinnaiyan2,4, and
  13. Pavan Reddy1
  1. 1Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
  2. 2Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
  3. 3Department of Internal Medicine, University of Toledo Medical Center, Toledo, OH; and
  4. 4Howard Hughes Institute, University of Michigan, Ann Arbor, MI

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.

  • Submitted December 15, 2010.
  • Accepted March 28, 2011.
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