Regulation of NF-κB-dependent gene expression by ligand-induced endocytosis of the interleukin-1 receptor

Cell Signal. 2013 Jan;25(1):214-28. doi: 10.1016/j.cellsig.2012.09.028. Epub 2012 Sep 28.

Abstract

Interleukin-1 (IL-1) induces the internalization of its cognate receptor from the plasma membrane. However, it has remained elusive as to how this mechanism affects the IL-1-induced signal transduction. In this study, we used small-molecule inhibitors of receptor endocytosis to analyze the effects on IL-1-induced signal transduction pathways. We demonstrate that the inhibition of endocytosis down-modulates IL-1-induced NF-κB-dependent gene expression at a level downstream of nuclear translocation and DNA binding of NF-κB. Moreover, we report that the reduced NF-κB-dependent gene expression disrupts feedback inhibition loops terminating the activation of mitogen-activated protein kinases and down-regulating the expression of IL-1-induced mRNAs. Collectively, we show that the inhibition of endocytosis causes a dysregulation of IL-1-induced signal transduction and gene expression demonstrating an important role for receptor internalization in IL-1 signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA / metabolism
  • Down-Regulation / drug effects
  • Dynamins / antagonists & inhibitors
  • Dynamins / metabolism
  • Endocytosis / drug effects*
  • HEK293 Cells
  • Humans
  • Hydrazones / pharmacology
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism
  • Interleukin-1 / pharmacology*
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Ligands
  • Mice
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Receptors, Interleukin-1 / metabolism*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects

Substances

  • Hydrazones
  • I-kappa B Proteins
  • Interleukin-1
  • Interleukin-8
  • Ligands
  • N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Receptors, Interleukin-1
  • Recombinant Proteins
  • NF-KappaB Inhibitor alpha
  • DNA
  • Mitogen-Activated Protein Kinases
  • Dynamins