Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes

J Biol Chem. 1999 Mar 19;274(12):7611-4. doi: 10.1074/jbc.274.12.7611.


Bacterial lipopolysaccharide (LPS)-mediated immune responses, including activation of monocytes, macrophages, and endothelial cells, play an important role in the pathogenesis of Gram-negative bacteria-induced sepsis syndrome. Activation of NF-kappaB is thought to be required for cytokine release from LPS-responsive cells, a critical step for endotoxic effects. Here we investigated the role and involvement of interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha) signal transducer molecules in LPS signaling in human dermal microvessel endothelial cells (HDMEC) and THP-1 monocytic cells. LPS stimulation of HDMEC and THP-1 cells initiated an IL-1 receptor-like NF-kappaB signaling cascade. In transient cotransfection experiments, dominant negative mutants of the IL-1 signaling pathway, including MyD88, IRAK, IRAK2, and TRAF6 inhibited both IL-1- and LPS-induced NF-kappaB-luciferase activity. LPS-induced NF-kappaB activation was not inhibited by a dominant negative mutant of TRAF2 that is involved in TNF signaling. LPS-induced activation of NF-kappaB-responsive reporter gene was not inhibited by IL-1 receptor antagonist. TLR2 and TLR4 were expressed on the cell surface of HDMEC and THP-1 cells. These findings suggest that a signal transduction molecule in the LPS receptor complex may belong to the IL-1 receptor/toll-like receptor (TLR) super family, and the LPS signaling cascade uses an analogous molecular framework for signaling as IL-1 in mononuclear phagocytes and endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Antigens, Differentiation / metabolism
  • Cells, Cultured
  • Endothelium / drug effects
  • Endothelium / metabolism
  • Humans
  • Interleukin-1 / physiology*
  • Interleukin-1 Receptor-Associated Kinases
  • Lipopolysaccharides / pharmacology*
  • Molecular Sequence Data
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • Myeloid Differentiation Factor 88
  • NF-kappa B / metabolism*
  • Protein Kinases / metabolism
  • Proteins / metabolism
  • Receptors, Immunologic*
  • Signal Transduction / drug effects*
  • Skin / drug effects
  • Skin / metabolism*
  • TNF Receptor-Associated Factor 6
  • Transfection


  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Interleukin-1
  • Lipopolysaccharides
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Proteins
  • Receptors, Immunologic
  • TNF Receptor-Associated Factor 6
  • Protein Kinases
  • Interleukin-1 Receptor-Associated Kinases