Abstract
Stimulation of the APC by Porphyromonas gingivalis LPS has been shown to result in the production of certain pro- and anti-inflammatory cytokines. However, the signaling pathways that regulate these processes are currently unknown. In the present study, the role of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway in regulating P. gingivalis LPS-induced production of IL-10, IL-12 p40, and IL-12 p70 by human monocytes was investigated. P. gingivalis LPS selectively activates the PI3K-Akt pathway via Toll-like receptor 2, and inhibition of this pathway results in an abrogation of extracellular signal-regulated kinase 1/2 phosphorylation, whereas the activation of p38 and c-Jun N-terminal kinase 1/2 kinases were unaffected. Analysis of cytokine production following stimulation of monocytes with P. gingivalis LPS revealed that inhibition of the PI3K pathway differentially regulated IL-10 and IL-12 synthesis. IL-10 production was suppressed, whereas IL-12 levels were enhanced. Inhibition of P. gingivalis LPS-mediated activation of the PI3K-Akt pathway resulted in a pronounced augmentation of NF-kappaB p65 that was independent of IkappaB-alpha degradation. Furthermore, the ability of the PI3K-Akt pathway to modulate IL-10 and IL-12 production appears to be mediated by the selective suppression of extracellular signal-regulated kinase 1/2 activity, as the MEK1 inhibitor PD98059 closely mimicked the effects of wortmannin and LY294002 to differentially regulate IL-10 and IL-12 production by P. gingivalis LPS-stimulated monocytes. These studies provide new insight into how engagement of the PI3K-Akt pathway by P. gingivalis LPS affects the induction of key immunoregulatory cytokines that control both qualitative and quantitative aspects of innate and adaptive immunity.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Cells, Cultured
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Enzyme Activation / drug effects
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Enzyme Activation / immunology
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Enzyme Inhibitors / pharmacology
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Humans
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Interleukin-10 / antagonists & inhibitors
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Interleukin-10 / biosynthesis*
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Interleukin-10 / physiology
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Interleukin-12 / antagonists & inhibitors
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Interleukin-12 / biosynthesis*
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Interleukin-12 Subunit p40
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Lipopolysaccharides / pharmacology*
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MAP Kinase Signaling System / immunology*
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Membrane Glycoproteins / physiology
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinase 9
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Monocytes / enzymology
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Monocytes / immunology
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Monocytes / metabolism
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NF-kappa B / metabolism
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Phosphatidylinositol 3-Kinases / physiology*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Porphyromonas gingivalis / immunology*
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Protein Serine-Threonine Kinases / physiology*
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Protein Subunits / antagonists & inhibitors
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Protein Subunits / biosynthesis
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-akt
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Receptors, Cell Surface / physiology
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Toll-Like Receptor 2
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Toll-Like Receptors
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Transcriptional Activation / immunology
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Up-Regulation / drug effects
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Up-Regulation / immunology
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p38 Mitogen-Activated Protein Kinases
Substances
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Enzyme Inhibitors
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Interleukin-12 Subunit p40
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Lipopolysaccharides
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Membrane Glycoproteins
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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Protein Subunits
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Proto-Oncogene Proteins
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Receptors, Cell Surface
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TLR2 protein, human
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Toll-Like Receptor 2
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Toll-Like Receptors
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Interleukin-10
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Interleukin-12
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Mitogen-Activated Protein Kinase 9
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases