Adrenomedullin suppresses interleukin-1beta-induced tumor necrosis factor-alpha production in Swiss 3T3 cells.
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.
Isumi
Y
Y
National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka, Japan.
Kubo
A
A
Katafuchi
T
T
Kangawa
K
K
Minamino
N
N
D016475:3T3 Cells; D053607:Adrenomedullin; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D010455:Peptides / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007375:Interleukin-1; D008565:Membrane Proteins; D010455:Peptides; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D053607:Adrenomedullin; D019833:Genistein; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one