Lithium induces NF-kappa B activation and interleukin-8 production in human intestinal epithelial cells.
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.
Németh
Zoltán H
ZH
Department of Surgery, UMD-New Jersey Medical School, Newark, New Jersey 07103, USA.
Deitch
Edwin A
EA
Szabó
Csaba
C
Fekete
Zoltán
Z
Hauser
Carl J
CJ
Haskó
György
G
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D004232:Diuretics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000378:metabolism; D007422:Intestines / Q000166:cytology*; D008094:Lithium / Q000097:blood / Q000494:pharmacology*; D018021:Lithium Chloride / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008928:Mitochondria / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D000316:Adrenergic alpha-Agonists; D004232:Diuretics; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D017923:Sodium-Hydrogen Exchangers; D012313:RNA; D008094:Lithium; D008156:Luciferases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018021:Lithium Chloride