Abstract
This study compared the effects of intracellular pathway inhibitors on tumor necrosis factor-alpha (TNF-alpha) release from human monocytes. Cells were stimulated with peptidoglycan (PG) from Staphylococcus epidermidis or with Escherichia coli lipopolysaccharide (LPS), both in the presence of 10% human serum. Of 10 substances tested, only the protein tyrosine kinase inhibitor tyrphostin AG 126 discriminated significantly between PG and LPS: TNF-alpha release induced by PG, but not by LPS, was dose-dependently suppressed. The results obtained with other modulatory substances, including different protein kinase and G protein inhibitors, suggest that calmodulin-dependent protein kinase, protein tyrosine kinase, and a cholera-toxin-sensitive G protein are involved in both PG- and LPS-induced TNF-alpha release. Further, drugs such as pentoxifylline, chloroquine, and the antioxidant apocynin similarly inhibited TNF-alpha release by PG- as well as LPS-stimulated cells.
MeSH terms
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Acetophenones / pharmacology
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Alkaloids / pharmacology
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Antimalarials / pharmacology
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Cell Communication / physiology*
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Chloroquine / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Escherichia coli
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GTP-Binding Proteins / antagonists & inhibitors
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GTP-Binding Proteins / metabolism
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Humans
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Isoquinolines / pharmacology
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Lipopolysaccharides / pharmacology*
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Monocytes / drug effects
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Monocytes / metabolism*
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Pentoxifylline / pharmacology
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Peptidoglycan / pharmacology*
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Piperazines / pharmacology
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Protein Kinase Inhibitors
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Protein Kinases / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Signal Transduction / physiology*
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Staphylococcus epidermidis
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Staurosporine
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Sulfonamides / pharmacology
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Tumor Necrosis Factor-alpha / metabolism*
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Vasodilator Agents / pharmacology
Substances
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Acetophenones
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Alkaloids
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Antimalarials
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Enzyme Inhibitors
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Isoquinolines
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Lipopolysaccharides
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Peptidoglycan
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Piperazines
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Protein Kinase Inhibitors
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Sulfonamides
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Tumor Necrosis Factor-alpha
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Vasodilator Agents
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W 7
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Chloroquine
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acetovanillone
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Protein Kinases
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Protein-Tyrosine Kinases
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GTP-Binding Proteins
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Staurosporine
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Pentoxifylline