Abstract
We demonstrated that adrenomedullin (AM) inhibited interleukin-1beta-induced tumor necrosis factor-alpha (TNF-alpha) secretion and gene transcription in Swiss 3T3 fibroblasts maximally to 23% and 18% of control, while the other peptides elevating intracellular cAMP levels elicited much weaker effects. AM rapidly reduced the gene transcript level of TNF-alpha, inducing a maximal effect within 1 h. The inhibitory effect of AM was restored with an AM receptor antagonist as well as a cAMP-dependent protein kinase inhibitor. These findings indicate that AM is a potent and quick suppressor of TNF-alpha production in Swiss 3T3 cells acting through the cAMP protein kinase A pathway. As TNF-alpha is a major inflammatory cytokine and stimulates AM production in fibroblasts, AM is deduced to be an autocrine or paracrine factor suppressing inflammation through the inhibition of TNF-alpha production.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Adrenomedullin
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Animals
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Cell Line
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Flavonoids / pharmacology
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Genistein / pharmacology
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Interleukin-1 / antagonists & inhibitors*
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Interleukin-1 / genetics
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Interleukin-1 / pharmacology
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Membrane Proteins / antagonists & inhibitors
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Mice
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Peptides / pharmacology*
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Polymerase Chain Reaction
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Receptors, Adrenomedullin
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Receptors, Peptide*
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Time Factors
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Transcription, Genetic / drug effects
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Tumor Necrosis Factor-alpha / biosynthesis*
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Tumor Necrosis Factor-alpha / genetics
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Vasodilator Agents / pharmacology
Substances
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Enzyme Inhibitors
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Flavonoids
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Interleukin-1
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Membrane Proteins
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Peptides
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Receptors, Adrenomedullin
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Receptors, Peptide
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Tumor Necrosis Factor-alpha
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Vasodilator Agents
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Adrenomedullin
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Genistein
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one