Lipopolysaccharide-induced cytokine production in human monocytes: role of tyrosine phosphorylation in transmembrane signal transduction

Eur J Immunol. 1994 Jun;24(6):1278-84. doi: 10.1002/eji.1830240606.


The signal transduction events that follow the binding of lipopolysaccharide (LPS) to the macrophage cell surface are not well defined. In the current studies LPS was found to induce alterations in phosphorylation of monocyte proteins on tyrosine. Herbimycin A and genistein, inhibitors of tyrosine kinases, markedly attenuated LPS-induced tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) protein and mRNA production. Reciprocally, the tyrosine phosphatase inhibitor sodium orthovanadate enhanced LPS-induced production of TNF-alpha. LPS induced a concentration-dependent increase in tyrosine phosphorylation of several proteins, which paralleled and preceded the onset of LPS-induced TNF-alpha production. LPS stimulation had different but reproducible effects on three members of the src family of tyrosine kinases. Both Hck and Lyn kinase activity increased before the onset of TNF-alpha production, consistent with their participation in the observed LPS-induced tyrosine phosphoprotein accumulation. In contrast, Yes kinase activity was not affected. These observations were made at concentrations of LPS that required serum rich in LPS-binding protein and the monocyte surface antigen CD14 for TNF-alpha production. These data indicate that tyrosine kinases and phosphatases are involved in the signal transduction cascade by which LPS induces production of TNF-alpha and IL-6 by human monocytes, and suggest that Lyn and Hck are candidate participants in this process.

Publication types

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

MeSH terms

  • Acute-Phase Proteins*
  • Antigens, CD / physiology
  • Antigens, Differentiation, Myelomonocytic / physiology
  • Benzoquinones
  • Blotting, Northern
  • Carrier Proteins / physiology
  • Cytokines / biosynthesis*
  • Humans
  • In Vitro Techniques
  • Interleukin-6 / biosynthesis
  • Lactams, Macrocyclic
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides / immunology*
  • Membrane Glycoproteins*
  • Monocytes / immunology
  • Monocytes / physiology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / physiology*
  • Quinones / pharmacology
  • RNA, Messenger / isolation & purification
  • Rifabutin / analogs & derivatives
  • Signal Transduction / immunology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Vanadates / pharmacology


  • Acute-Phase Proteins
  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Benzoquinones
  • Carrier Proteins
  • Cytokines
  • Interleukin-6
  • Lactams, Macrocyclic
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Quinones
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • lipopolysaccharide-binding protein
  • Rifabutin
  • Vanadates
  • herbimycin
  • Protein-Tyrosine Kinases