Abstract
In this study, we examined the signal transduction of dibutyryl cyclic adenosine monophosphate (dBcAMP) to stimulate the release of nitric oxide (NO) and interleukin-6 (IL-6) from J774 macrophages. These actions of dBcAMP were diminished by the presence of the inhibitors of protein kinase A (PKA), protein kinase C (PKC), p38 MAPK and nuclear factor-kappa B (NF-kappaB). In contrast, Go 6976 and PD98059 had no significant effects. Consistently, dBcAMP caused membrane translocation of PKCbetaII, delta, mu, lambda and zeta isoforms, and increased atypical protein kinase C (aPKC) and p38 MAPK activities. The nuclear translocation and DNA-binding study revealed that dBcAMP stimulated NF-kappaB, activator protein-1 (AP-1), and CAAT/enhancer-binding protein (c/EBPbeta). Via PKA, PKC and p38 MAPK-dependent signals, dBcAMP also induced inhibitory subunit of NF-kappaB (IkappaB) degradation, IkappaB kinase (IKK) activation, nuclear translocation of NF-kappaB subunit p65 and its association with the CREB-binding protein (CBP). These results illustrate that PKA activation in macrophages is able to stimulate PKC and p38 MAPK, which lead to IKK-dependent NF-kappaB activation and contribute to the induction of inducible nitric oxide synthase (iNOS) and IL-6 genes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bucladesine / pharmacology*
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Carbazoles / pharmacology
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Carrier Proteins / pharmacology
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Cell Line
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Enzyme Induction / drug effects
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Gene Expression Regulation, Enzymologic / drug effects
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I-kappa B Kinase
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Indoles / pharmacology
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Interleukin-6 / biosynthesis*
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Intracellular Signaling Peptides and Proteins*
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Macrophages / metabolism*
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / metabolism
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Nitric Oxide Synthase / biosynthesis*
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Nitric Oxide Synthase Type II
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Phosphorylation / drug effects
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction* / drug effects
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p38 Mitogen-Activated Protein Kinases
Substances
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Carbazoles
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Carrier Proteins
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Enzyme Inhibitors
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Flavonoids
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Indoles
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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protein kinase modulator
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Go 6976
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Bucladesine
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Protein Serine-Threonine Kinases
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Chuk protein, mouse
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I-kappa B Kinase
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Ikbkb protein, mouse
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Ikbke protein, mouse
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Protein Kinase C
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one