A newly identified microRNA, mmu-miR-7578, functions as a negative regulator on inflammatory cytokines tumor necrosis factor-α and interleukin-6 via targeting Egr1 in vivo

J Biol Chem. 2013 Feb 8;288(6):4310-20. doi: 10.1074/jbc.M112.351197. Epub 2012 Nov 26.

Abstract

Appropriate innate immune responses are required to protect an organism against foreign pathogens, and the immune response must be tightly controlled. Here, we report a new microRNA (miRNA) identified from a small RNA library from the epididymis, termed miR-7578, that acts as a negative regulator of inflammatory responses. It was abundantly expressed in immune-related organs and induced by lipopolysaccharide in the lung and epididymis, as well as macrophages stimulated with diverse Toll-like receptor ligands, in an NF-κB-dependent manner. mmu-miR-7578 inhibited the release of pro-inflammatory cytokines, including TNFα and IL6, by regulating its target gene Egr1, which encodes a transcription factor that activates TNFα and NF-κB expression. Transgenic mice overexpressing mmu-miR-7578 displayed higher resistance to endotoxin shock and lower plasma levels of TNFα and IL6, indicating that this miRNA acted as a negative molecule of immune response. In sum, we report a previously uncharacterized LPS-responsive miRNA that controls inflammatory response in a feedback loop by fine-tuning a key transcription factor in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Early Growth Response Protein 1 / biosynthesis*
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / immunology
  • Gene Expression Regulation*
  • Interleukin-6 / biosynthesis*
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Lipopolysaccharides / pharmacology
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / immunology
  • MicroRNAs / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Interleukin-6
  • Lipopolysaccharides
  • MicroRNAs
  • NF-kappa B
  • Tumor Necrosis Factor-alpha