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
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Research Support, Non-U.S. Gov't
MeSH terms
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Cells, Cultured
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / metabolism*
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Enzyme Inhibitors / pharmacology
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Feedback, Physiological / drug effects
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Feedback, Physiological / physiology
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Granulocyte Colony-Stimulating Factor / pharmacology*
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Humans
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Interleukin-10 / metabolism
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Interleukin-10 / pharmacology
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Janus Kinase 2
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Lipopolysaccharides / pharmacology*
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Monocytes / drug effects
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Monocytes / immunology
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Monocytes / metabolism*
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Neutrophils / drug effects
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Neutrophils / immunology
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Neutrophils / metabolism
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Phosphorylation / drug effects
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Protein-Tyrosine Kinases / drug effects
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins*
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Receptors, Granulocyte Colony-Stimulating Factor / metabolism
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STAT3 Transcription Factor
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Trans-Activators / drug effects
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Trans-Activators / metabolism*
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Tumor Necrosis Factor-alpha / drug effects
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Lipopolysaccharides
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Proto-Oncogene Proteins
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Receptors, Granulocyte Colony-Stimulating Factor
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STAT3 Transcription Factor
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STAT3 protein, human
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Trans-Activators
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Tumor Necrosis Factor-alpha
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Interleukin-10
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Granulocyte Colony-Stimulating Factor
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Janus Kinase 2