Modulation of TLR signalling by the C-terminal Src kinase (Csk) in macrophages

Daisuke Aki, Ryuichi Mashima, Kazuko Saeki, Yasumasa Minoda, Moriyasu Yamauchi, Akihiko Yoshimura

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

In macrophages and monocytes, lipopolysaccharide (LPS) triggers the production of pro-inflammatory cytokine through Toll-like receptor (TLR) 4. Although major TLR signalling pathways are mediated by serine or threonine kinases including IKK, TAK1, p38 and JNKs, a number of reports suggested that tyrosine phosphorylation of intracellular proteins is involved in LPS signalling. Here, we identified several tyrosine-phosphorylated proteins using mass spectrometric analysis in response to LPS stimulation. Among these proteins, we characterized C-terminal Src kinase (Csk), which negatively regulates Src-like kinases in RAW 264.7 cells using RNAi knockdown technology. Unexpectedly, LPS-induced CD40 activation and the secretion of pro-inflammatory cytokine such as IL-6 and TNF-α, was down-regulated in Csk knockdown cells. Furthermore, overall cellular tyrosine phosphorylation and TLR4-mediated activation of IκB-α, Erk and p38 but not of JNK, were also down-regulated in Csk knockdown cells. The protein expression levels of a tyrosine kinase, Fgr, were reduced in Csk knockdown cells, suggesting that Csk is a critical regulator of TLR4-mediated signalling by modifying the levels of Src-like kinases.

Original languageEnglish
Pages (from-to)357-368
Number of pages12
JournalGenes to Cells
Volume10
Issue number4
DOIs
Publication statusPublished - 2005 Apr
Externally publishedYes

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Toll-Like Receptors
Macrophages
Lipopolysaccharides
Tyrosine
src-Family Kinases
Phosphorylation
Cytokines
Toll-Like Receptor 4
Proteins
Protein-Serine-Threonine Kinases
RNA Interference
Protein C
Protein-Tyrosine Kinases
Monocytes
Interleukin-6
CSK tyrosine-protein kinase
Technology

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Modulation of TLR signalling by the C-terminal Src kinase (Csk) in macrophages. / Aki, Daisuke; Mashima, Ryuichi; Saeki, Kazuko; Minoda, Yasumasa; Yamauchi, Moriyasu; Yoshimura, Akihiko.

In: Genes to Cells, Vol. 10, No. 4, 04.2005, p. 357-368.

Research output: Contribution to journalArticle

Aki, Daisuke ; Mashima, Ryuichi ; Saeki, Kazuko ; Minoda, Yasumasa ; Yamauchi, Moriyasu ; Yoshimura, Akihiko. / Modulation of TLR signalling by the C-terminal Src kinase (Csk) in macrophages. In: Genes to Cells. 2005 ; Vol. 10, No. 4. pp. 357-368.
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