Abstract
Microglial cells actively participate in proinflammatory responses in the CNS. Upon stimulation with the bacterial LPS, microglial cells express a functional formyl peptide receptor 2 which mediates the chemotactic and activating effects of a variety of polypeptide agonists including amyloid beta (Abeta(1-42)), a critical pathogenic agent in Alzheimer's disease. In the present study, we found that LPS-induced expression and function of formyl peptide receptor 2 in microglial cells was markedly inhibited by IL-4, a Th2-type cytokine. Our effort to elucidate the mechanistic basis revealed that IL-4 attenuated LPS-stimulated activation of NF-kappaB, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinase, and the effect of IL-4 was associated with a phosphoinositide 3-kinase pathway-dependent increase in serine/threonine phosphatase activity. These results suggest that IL-4 may play an important role in the maintenance of homeostasis of CNS and in the regulation of the disease process characterized by microglial activation in response to proinflammatory stimulants.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Activating Transcription Factor 2
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Animals
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Antigens, Surface / metabolism
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Cell Line
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Cell Movement / immunology
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Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors
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Cyclic AMP Response Element-Binding Protein / metabolism
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Down-Regulation / immunology*
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Enzyme Activation / immunology
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation / immunology
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Interleukin-4 / pharmacology*
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / pharmacology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microglia / cytology
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Microglia / enzymology*
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Microglia / immunology*
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Microglia / metabolism
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / biosynthesis
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinases / biosynthesis
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Phosphatidylinositol 3-Kinases / physiology
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Phosphoprotein Phosphatases / metabolism
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Phosphoprotein Phosphatases / physiology
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Phosphorylation
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / biosynthesis
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Protein Isoforms / genetics
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Protein Isoforms / physiology
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Receptors, Formyl Peptide / antagonists & inhibitors*
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Receptors, Formyl Peptide / biosynthesis*
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Receptors, Formyl Peptide / genetics
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Receptors, Formyl Peptide / physiology
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism
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p38 Mitogen-Activated Protein Kinases
Substances
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Activating Transcription Factor 2
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Antigens, Surface
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Cyclic AMP Response Element-Binding Protein
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Enzyme Inhibitors
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Lipopolysaccharides
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NF-kappa B
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Protein Isoforms
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Receptors, Formyl Peptide
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Transcription Factors
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formyl peptide receptor 2, mouse
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Interleukin-4
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Phosphatidylinositol 3-Kinases
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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 Kinases
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p38 Mitogen-Activated Protein Kinases
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Phosphoprotein Phosphatases