Abstract
Lithium has been documented to regulate apoptosis and apoptotic gene expression via NF-kappa B and mitogen-activated protein (MAP) kinase-dependent mechanisms. Since both NF-kappa B and MAP kinases are also important mediators of inflammatory gene expression, we investigated the effect of lithium on NF-kappa B- and MAP kinase-mediated inflammatory gene expression. Incubation of human intestinal epithelial cells with lithium induced both enhanced NF-kappa B DNA binding and NF-kappa B-dependent transcriptional activity. In addition, lithium stimulated activation of both the p38 and p42/44 MAP kinases. This lithium-induced up-regulation of NF-kappa B and MAP kinase activation was associated with an enhancement of interleukin-8 mRNA accumulation as well as an increase in interleukin-8 protein release. These proinflammatory effects of lithium were, in large part, mediated by activation of Na(+)/H(+) exchangers, because selective blockade of Na(+)/H(+) exchangers prevented the lithium-induced intestinal cell inflammatory response. These results demonstrate that lithium stimulates inflammatory gene expression via NF-kappa B and MAP kinase activation.
MeSH terms
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Adrenergic alpha-Agonists / pharmacology
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Blotting, Western
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Cell Line
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Diuretics / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Epithelial Cells / metabolism*
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Humans
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Interleukin-8 / biosynthesis*
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Interleukin-8 / metabolism
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Intestines / cytology*
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Lithium / blood
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Lithium / pharmacology*
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Lithium Chloride / pharmacology
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Luciferases / metabolism
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MAP Kinase Signaling System
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Mitochondria / metabolism
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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 Kinases / metabolism
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NF-kappa B / metabolism*
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Protein Binding
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RNA / metabolism
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sodium-Hydrogen Exchangers / metabolism
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Transcription, Genetic
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Transfection
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Tumor Cells, Cultured
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Up-Regulation
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p38 Mitogen-Activated Protein Kinases
Substances
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Adrenergic alpha-Agonists
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Diuretics
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Enzyme Inhibitors
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Interleukin-8
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NF-kappa B
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RNA, Messenger
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Sodium-Hydrogen Exchangers
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RNA
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Lithium
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Luciferases
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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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Lithium Chloride