Thalidomide inhibits lipopolysaccharide-induced nitric oxide production and prevents lipopolysaccharide-mediated lethality in mice

FEMS Immunol Med Microbiol. 2009 Aug;56(3):204-11. doi: 10.1111/j.1574-695X.2009.00567.x. Epub 2009 May 6.

Abstract

The effect of thalidomide on lipopolysaccharide-induced nitric oxide (NO) production was studied using RAW 264.7 macrophage-like cells. Thalidomide significantly inhibited lipopolysaccharide-induced NO production via reduced expression of an inducible NO synthase. Thalidomide reduced the phosphorylation of the p65 nuclear factor-kappaB subunit, inhibitory kappaB (IkappaB) and IkappaB kinase in lipopolysaccharide-stimulated cells. However, thalidomide did not affect the expression of interferon-beta (IFN-beta) and interferon regulatory factor-1 in response to lipopolysaccharide. Further, thalidomide inhibited the MyD88 augmentation in lipopolysaccharide-stimulated cells, whereas it did not alter the expression of TIR domain-containing adaptor-inducing IFN-beta in the MyD88-independent pathway. Thalidomide significantly inhibited the NO production in response to Pam(3)Cys, CpG DNA and imiquimod as MyD88-dependent Toll-like receptor (TLR) ligands, but not polyI:C as a MyD88-independent TLR ligand. Therefore, thalidomide was suggested to inhibit lipopolysaccharide-induced NO production via downregulation of the MyD88-dependent signal pathway. The anti-inflammatory action of thalidomide might be involved in the prevention of lipopolysaccharide-mediated lethality in mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Survival
  • Down-Regulation
  • I-kappa B Kinase / metabolism
  • I-kappa B Proteins / metabolism
  • Immunosuppressive Agents / pharmacology*
  • Lipopolysaccharides / immunology*
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88 / antagonists & inhibitors
  • Nitric Oxide / antagonists & inhibitors*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Phosphorylation
  • Survival Analysis
  • Thalidomide / pharmacology*
  • Transcription Factor RelA / metabolism

Substances

  • I-kappa B Proteins
  • Immunosuppressive Agents
  • Lipopolysaccharides
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Transcription Factor RelA
  • Nitric Oxide
  • Thalidomide
  • Nitric Oxide Synthase
  • I-kappa B Kinase