Abstract
NO production by macrophages in response to lipoteichoic acid (LTA) and a synthetic lipopeptide (Pam3CSK4) was investigated. LTA and Pam3CSK4 induced the production of both TNF-alpha and NO. Inhibitors of platelet-activating factor receptor (PAFR) blocked LTA- or Pam3CSK4-induced production of NO but not TNF-alpha. Jak2 tyrosine kinase inhibition blocked LTA-induced production of NO but not TNF-alpha. PAFR inhibition blocked phosphorylation of Jak2 and STAT1, a key factor for expressing inducible NO synthase. In addition, LTA did not induce IFN-beta expression, and p38 mitogen-activated protein serine kinase was necessary for LTA-induced NO production but not for TNF-alpha production. These findings suggest that Gram-positive bacteria induce NO production using a PAFR signaling pathway to activate STAT1 via Jak2. This PAFR/Jak2/STAT1 signaling pathway resembles the IFN-beta, type I IFNR/Jak/STAT1 pathway described for LPS. Consequently, Gram-positive and Gram-negative bacteria appear to have different but analogous mechanisms for NO production.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Enzyme Inhibitors / pharmacology
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Gram-Positive Bacterial Infections / immunology*
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Janus Kinase 2
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Lipopolysaccharides / immunology
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Lipopolysaccharides / metabolism*
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Nitric Oxide / biosynthesis*
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Peptides / metabolism
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Platelet Membrane Glycoproteins / immunology
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Platelet Membrane Glycoproteins / metabolism*
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Protein-Tyrosine Kinases / drug effects
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Protein-Tyrosine Kinases / immunology
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / immunology
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Proto-Oncogene Proteins / metabolism*
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Receptors, G-Protein-Coupled / immunology
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Receptors, G-Protein-Coupled / metabolism*
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STAT1 Transcription Factor / drug effects
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STAT1 Transcription Factor / immunology
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STAT1 Transcription Factor / metabolism
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Teichoic Acids / immunology
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Teichoic Acids / metabolism*
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / drug effects
Substances
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Enzyme Inhibitors
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Lipopolysaccharides
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Peptides
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Platelet Membrane Glycoproteins
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Proto-Oncogene Proteins
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Receptors, G-Protein-Coupled
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STAT1 Transcription Factor
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Teichoic Acids
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Tumor Necrosis Factor-alpha
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platelet activating factor receptor
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Nitric Oxide
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lipoteichoic acid
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Protein-Tyrosine Kinases
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Jak2 protein, mouse
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Janus Kinase 2