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Protein-tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes

Academic Article
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Overview

authors

  • Geng, Y.
  • Zhang, B. P.
  • Lotz, Martin

publication date

  • December 1993

journal

  • Journal of Immunology  Journal

abstract

  • Bacterial LPS induce production of cytokines such as IL-1, IL-6, and TNF in mononuclear phagocytes, and this represents a central component in the pathogenesis of septic shock syndrome. However, the mechanisms by which LPS activates these cells to express cytokines are not completely characterized. The present study addressed the role of different protein kinases in the LPS induction of cytokines. It is shown that LPS induced a 12- to 16-fold increase in IL-1 beta, IL-6, and TNF-alpha mRNA levels, and this was completely or more than 80% blocked by the protein tyrosine kinase specific inhibitors herbimycin A and genistein at the concentrations of 1.7 and 37 microM, respectively. Protein kinase C inhibition by staurosporine reduced LPS induction of TNF-alpha, whereas it had no effects on IL-6 and IL-1 beta. Inhibition of protein kinase A by H89 reduced IL-6 mRNA levels but did not detectably change IL-1 beta or TNF-alpha mRNA levels. In contrast, LPS did not increase leukemia inhibitory factor mRNA, which was constitutively expressed and not significantly reduced by these inhibitors. In addition to cytokine mRNA levels, LPS-induced IL-6 protein synthesis and IL-6 bioactivity were also reduced to baseline levels by the PTK inhibitors herbimycin A and genistein. Both PTK inhibitors also reduced the LPS activation of nuclear factor-kappa B (NF-kappa B), which is a transcription factor involved in the expression of cytokine genes such as IL-6 and TNF-alpha. The activation of NF-kappa B was also reduced by H89, whereas staurosporine had no effect on this response. In summary, these findings suggest that protein kinase C and protein kinase A appear to have selective effects in the LPS induction of cytokines, whereas PTK is required for LPS induction of a broad spectrum of cytokines and NF-kappa B activation in monocytes.

subject areas

  • Base Sequence
  • Cyclic AMP-Dependent Protein Kinases
  • Cytokines
  • Enzyme Activation
  • Humans
  • In Vitro Techniques
  • Interleukin-1
  • Interleukin-6
  • Lipopolysaccharides
  • Molecular Sequence Data
  • Monocytes
  • NF-kappa B
  • Oligonucleotide Probes
  • Protein Kinase C
  • Protein-Tyrosine Kinases
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
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Identity

International Standard Serial Number (ISSN)

  • 0022-1767

PubMed ID

  • 8258685
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Additional Document Info

start page

  • 6692

end page

  • 6700

volume

  • 151

issue

  • 12

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