Abstract
Florfenicol, an antibiotic commonly used to treat infections, has previously been shown to modulate lipopolysaccharide (LPS)-induced early cytokine responses by blocking the nuclear factor-κB (NF-κB) pathway. In this study, we investigated the effects of florfenicol on nitric oxide (NO) and prostaglandin E₂ (PGE₂) production as well as on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in LPS-stimulated murine RAW 264.7 macrophages. We also analysed the effects of florfenicol on mitogen-activated protein kinase (MAPK) pathways. Florfenicol significantly inhibited LPS-induced NO and PGE₂ production. Consistent with these observations, mRNA and protein expression of iNOS and COX-2 were also inhibited by florfenicol in a dose-dependent manner. Furthermore, phosphorylation of p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) in LPS-stimulated RAW 264.7 cells was suppressed by florfenicol. However, c-Jun N-terminal kinase (JNK) phosphorylation remained unaffected. Using specific inhibitors of ERK and p38, we found that florfenicol may inhibit NO and PGE₂ mostly through ERK and p38 pathway. These results suggest that florfenicol inhibits NO and PGE₂ production in conjunction with an inhibition of iNOS and COX-2 expression, at least partially via suppression of ERK1/2 and p38 MAPK phosphorylation.
© 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Bacterial Agents / pharmacology*
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Cell Line
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Cyclooxygenase 2 / biosynthesis
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Cyclooxygenase 2 / genetics
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Dinoprostone / antagonists & inhibitors*
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Dinoprostone / genetics
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Dinoprostone / metabolism
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / pharmacology
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Imidazoles / pharmacology
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / immunology
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lipopolysaccharides / immunology
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Lipopolysaccharides / metabolism*
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Macrophages
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Mice
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / immunology
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Nitric Oxide / antagonists & inhibitors*
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Nitric Oxide / genetics
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Nitric Oxide / metabolism
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Nitric Oxide Synthase Type II / antagonists & inhibitors
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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Phosphorylation
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Pyridines / pharmacology
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Thiamphenicol / analogs & derivatives*
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Thiamphenicol / pharmacology
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / immunology
Substances
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Anti-Bacterial Agents
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Enzyme Inhibitors
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Imidazoles
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Lipopolysaccharides
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NF-kappa B
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Pyridines
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Nitric Oxide
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florfenicol
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Nitric Oxide Synthase Type II
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Cyclooxygenase 2
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Thiamphenicol
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Dinoprostone
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SB 203580