TAK1 mediates an activation signal from toll-like receptor(s) to nuclear factor-kappaB in lipopolysaccharide-stimulated macrophages

FEBS Lett. 2000 Feb 11;467(2-3):160-4. doi: 10.1016/s0014-5793(00)01146-7.

Abstract

Stimulation of monocytes/macrophages with lipopolysaccharide (LPS) results in activation of nuclear factor-kappaB (NF-kappaB), which plays crucial roles in regulating expression of many genes involved in the subsequent inflammatory responses. Here, we investigated roles of transforming growth factor-beta activated kinase 1 (TGF-TAK1), a mitogen-activated protein kinase kinase kinase (MAPKKK), in the LPS-induced signaling cascade. A kinase-negative mutant of TAK1 inhibited the LPS-induced NF-kappaB activation both in a macrophage-like cell line, RAW 264.7, and in human embryonic kidney 293 cells expressing toll-like receptor 2 or 4. Furthermore, we demonstrated that endogenous TAK1 is phosphorylated upon simulation of RAW 264.7 cells with LPS. These results indicate that TAK1 functions as a critical mediator in the LPS-induced signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Drosophila Proteins*
  • Humans
  • Lipopolysaccharides
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Macrophage Activation
  • Macrophages / drug effects
  • Macrophages / physiology*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • NF-kappa B / metabolism*
  • Phosphorylation / drug effects
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction
  • Toll-Like Receptor 2
  • Toll-Like Receptors
  • Transfection

Substances

  • Drosophila Proteins
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • NF-kappa B
  • Receptors, Cell Surface
  • TLR2 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptors
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7