Tyrosine kinase Syk associates with toll-like receptor 4 and regulates signaling in human monocytic cells

Immunol Cell Biol. Apr-May 2007;85(3):249-56. doi: 10.1038/sj.icb7100030. Epub 2007 Jan 16.

Abstract

Toll-like receptor 4 (TLR4) induces an innate immune response in mammals by recognizing lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria. In this study, we show that tyrosine kinase Syk constitutively associates with TLR4 in THP-1 cells. As previously reported in peripheral blood mononuclear cells, TLR4 gets inducibly tyrosine phosphorylated upon LPS engagement in THP-1 cells. Piceatannol, a pharmacological inhibitor of the tyrosine kinase Syk, abrogates TLR4 tyrosine phosphorylation at low doses. The kinetics of TLR4 tyrosine phosphorylation in THP-1 cells coincides with an early wave of Syk tyrosine phosphorylation. Additionally, serine threonine kinase interleukin-1 (IL1) receptor-associated kinase 1 (IRAK-1) is transiently recruited to the complex containing adaptor molecule MyD88, TLR4 and Syk within 1 min of LPS engagement and dissociates by 30 min. Finally, the inhibition of Syk with piceatannol has no effect on LPS-mediated release of cytokines IL6, IL1beta, tumor necrosis factor-alpha, neither on chemokines macrophage inhibitory protein (MIP)1alpha, MIP1beta, monocyte chemoattractant protein -1, IL8, Groalpha and RANTES. However, IL10 and IL12p40 releases are significantly inhibited. Our findings implicate Syk as a novel modulator of LPS-mediated TLR4 responses in human monocytic cells and shed insight into the kinetics of early complex formation upon LPS engagement.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Interleukin-10 / metabolism
  • Interleukin-12 / metabolism
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kinetics
  • Leukocytes, Mononuclear / metabolism
  • Lipopolysaccharides / immunology
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Myeloid Differentiation Factor 88 / metabolism
  • Phosphorylation
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction*
  • Stilbenes / pharmacology
  • Syk Kinase
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Stilbenes
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Interleukin-10
  • Interleukin-12
  • 3,3',4,5'-tetrahydroxystilbene
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Interleukin-1 Receptor-Associated Kinases