Beta-arrestins 1 and 2 differentially regulate LPS-induced signaling and pro-inflammatory gene expression

Mol Immunol. 2007 May;44(12):3092-9. doi: 10.1016/j.molimm.2007.02.009. Epub 2007 Apr 6.


Toll like receptors, the critical receptor family in innate immunity, have been shown to signal via both ERK 1/2 and transcription factor NFkappaB. beta-Arrestins 1 and 2 have recently been implicated in modulation of NFkappaB signaling and ERK 1/2 activation. Using a number of approaches: mouse embryonic fibroblasts (MEF) from wild-type (WT), beta-arrestins knockouts (KO), beta-arrestins 1 and 2 double KO, and MEFs with reconstituted WT beta-arrestins in the double KO cells, RNA interference (siRNA) specific knockdown of beta-arrestins, and overexpression of WT beta-arrestins, it was demonstrated that beta-arrestin 2 positively regulates LPS-induced ERK 1/2 activation and both beta-arrestins 1 and 2 negatively regulate LPS-induced NFkappaB activation. Also beta-arrestin 2 positively regulate LPS-induced IL-6 production and both beta-arrestins 1 and 2 positively regulate LPS-induced IL-8 production. The specific ERK1/2 inhibitor PD98059 significantly decreased LPS-induced IL-6 and IL-8 production suggesting that IL-6 and IL-8 production is, in part, mediated by ERK 1/2 activation. Over expression of wild type beta-arrestins 1 and 2 had no effect on LPS-induced ERK1/2 activation and LPS-induced IL-8 production suggesting that endogenous beta-arrestins 1 and 2 are sufficient to mediate maximum ERK 1/2 activity and IL-8 production. beta-Arrestins thus not only negatively regulate LPS-induced NFkappaB activation but also positively regulate ERK 1/2 activation and specific pro-inflammatory gene expression. Understanding the role of beta-arrestins in regulation of TLR signaling pathways may provide novel insights into control mechanisms for inflammatory gene expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arrestins / physiology*
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammation / genetics
  • Interleukins / biosynthesis
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • NF-kappa B / metabolism
  • Signal Transduction / drug effects
  • Transfection
  • beta-Arrestin 2
  • beta-Arrestins


  • ARRB2 protein, human
  • Arrb2 protein, mouse
  • Arrestins
  • Interleukins
  • Lipopolysaccharides
  • NF-kappa B
  • beta-Arrestin 2
  • beta-Arrestins
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3