Abstract
cAMP mediated signaling may play a suppressive role in immune response. We previously found that the cAMP-elevators (CTx and 8-Br-cAMP) inhibited IL-12, IL-la, IL-6 gene expression, but increased the transcriptional levels of IL-10 and IL-1Ra in LPS-treated murine peritoneal macrophages. The present study examined a possible molecular mechanism involved in cAMP elevators-induced inhibition of IL-12 p40 expression in response to LPS. Our data demonstrated that cAMP elevators downregulated IL-12 p40 mRNA expression and IL-12 p70 production in murine peritoneal macrophages. Subsequent studies revealed that cAMP-elevators blocked phosphorylation of p38 MAPK, but did not affect the activity of NF-kappaB binding to IL-12 promoter (-136/-112). This is the first report that cAMP elevators inhibit LPS-induced IL-12 production by a mechanism that is associated, at least in part, with p38-dependent inhibition by cAMP signaling pathways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites / drug effects
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Binding Sites / genetics
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Cells, Cultured
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Cyclic AMP / agonists
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Cyclic AMP / analogs & derivatives
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Cyclic AMP / metabolism*
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Immune System / immunology*
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Immune Tolerance / immunology*
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Inflammation / immunology*
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Interleukin-12 / genetics*
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Interleukin-12 / metabolism
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Interleukin-12 Subunit p40
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Lipopolysaccharides / pharmacology
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Macrophages / drug effects
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Macrophages / immunology*
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Macrophages / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinases / metabolism*
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NF-kappa B / metabolism
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Phosphorylation / drug effects
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Promoter Regions, Genetic / drug effects
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Promoter Regions, Genetic / genetics
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Protein Subunits / genetics*
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Protein Subunits / metabolism
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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p38 Mitogen-Activated Protein Kinases
Substances
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Interleukin-12 Subunit p40
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Lipopolysaccharides
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NF-kappa B
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Protein Subunits
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RNA, Messenger
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Interleukin-12
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Cyclic AMP
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases