MK2 targets AU-rich elements and regulates biosynthesis of tumor necrosis factor and interleukin-6 independently at different post-transcriptional levels

J Biol Chem. 2002 Feb 1;277(5):3065-8. doi: 10.1074/jbc.C100685200. Epub 2001 Dec 6.

Abstract

We demonstrate that lipopolysaccharide-induced tumor necrosis factor (TNF) biosynthesis becomes independent of MAPKAP kinase 2 (MK2) when the AU-rich element (ARE) of the TNF gene is deleted. In spleen cells and macrophages where TNF biosynthesis is restored as a result of this deletion, interleukin (IL)-6 biosynthesis is still dependent on MK2. In MK2-deficient macrophages the half-life of IL-6 mRNA is reduced more than 10-fold, whereas the half-life of TNF mRNA is only weakly decreased. It is shown that the stability of a reporter mRNA carrying the AU-rich 3'-untranslated region (3'-UTR) of IL-6 is increased by MK2. The data provide in vivo evidence that the AU-rich 3'-UTRs of TNF and IL-6 are downstream to MK2 signaling and make MK2 an essential component of mechanisms that regulate biosynthesis of IL-6 at the levels of mRNA stability, and of TNF mainly through TNF-ARE-dependent translational control.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Base Sequence
  • Binding Sites
  • Cells, Cultured
  • Gene Deletion
  • Gene Expression Regulation / drug effects
  • Heterogeneous Nuclear Ribonucleoprotein D0
  • Heterogeneous-Nuclear Ribonucleoprotein D*
  • Interleukin-6 / genetics*
  • Intracellular Signaling Peptides and Proteins
  • Kinetics
  • Lipopolysaccharides / pharmacology
  • Macrophage Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / deficiency
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Molecular Sequence Data
  • Protein Kinases*
  • Protein Serine-Threonine Kinases
  • RNA Processing, Post-Transcriptional
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism*
  • Sequence Deletion
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / genetics*

Substances

  • 3' Untranslated Regions
  • Heterogeneous Nuclear Ribonucleoprotein D0
  • Heterogeneous-Nuclear Ribonucleoprotein D
  • Hnrpd protein, mouse
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • RNA, Messenger
  • RNA-Binding Proteins
  • Tumor Necrosis Factor-alpha
  • Protein Kinases
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases