Selective activation of STAT3 in human monocytes stimulated by G-CSF: implication in inhibition of LPS-induced TNF-alpha production

Am J Physiol Cell Physiol. 2004 Jun;286(6):C1302-11. doi: 10.1152/ajpcell.00387.2003. Epub 2004 Jan 21.

Abstract

Lipopolysaccharide (LPS) induced tumor necrosis factor (TNF)-alpha production in human monocytes, which was dependent on activation of extracellular signal-regulated kinase (ERK), p38, c-Jun NH(2)-terminal kinase (JNK), and nuclear factor (NF)-kappa B. LPS-induced TNF-alpha production was inhibited by granulocyte colony-stimulating factor (G-CSF) and interleukin (IL)-10. G-CSF, like IL-10, exerted the inhibitory effect even when simultaneously added with LPS. Among the signaling pathways, signal transducer and activator of transcription 3 (STAT3) was selectively activated in monocytes stimulated by G-CSF or IL-10. G-CSF-mediated inhibition of LPS-induced TNF-alpha production as well as G-CSF-induced STAT3 phosphorylation and suppressor of cytokine signaling 3 mRNA expression were prevented by pretreatment of monocytes with AG-490, an inhibitor of Janus kinase 2. G-CSF did not affect LPS-induced activation of ERK, p38, JNK, and NF-kappa B, indicating that G-CSF affects the pathway downstream or independently of these signaling molecules. G-CSF-induced, but not IL-10-induced, STAT3 phosphorylation was attenuated in the presence of LPS. These findings suggest that G-CSF, like IL-10, inhibits LPS-induced TNF-alpha production in human monocytes through selective activation of STAT3, and the immunomodulation observed in vivo by G-CSF administration may be partly ascribed to the direct effect of G-CSF on monocyte functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Feedback, Physiological / drug effects
  • Feedback, Physiological / physiology
  • Granulocyte Colony-Stimulating Factor / pharmacology*
  • Humans
  • Interleukin-10 / metabolism
  • Interleukin-10 / pharmacology
  • Janus Kinase 2
  • Lipopolysaccharides / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Monocytes / drug effects
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / drug effects
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins*
  • Receptors, Granulocyte Colony-Stimulating Factor / metabolism
  • STAT3 Transcription Factor
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Trans-Activators / drug effects
  • Trans-Activators / metabolism*
  • Tumor Necrosis Factor-alpha / drug effects
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Proto-Oncogene Proteins
  • Receptors, Granulocyte Colony-Stimulating Factor
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Granulocyte Colony-Stimulating Factor
  • Protein-Tyrosine Kinases
  • JAK2 protein, human
  • Janus Kinase 2