Lithium induces NF-kappa B activation and interleukin-8 production in human intestinal epithelial cells

J Biol Chem. 2002 Mar 8;277(10):7713-9. doi: 10.1074/jbc.M109711200. Epub 2001 Dec 27.


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

  • Adrenergic alpha-Agonists / pharmacology
  • Blotting, Western
  • Cell Line
  • Diuretics / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / metabolism*
  • Humans
  • Interleukin-8 / biosynthesis*
  • Interleukin-8 / metabolism
  • Intestines / cytology*
  • Lithium / blood
  • Lithium / pharmacology*
  • Lithium Chloride / pharmacology
  • Luciferases / metabolism
  • MAP Kinase Signaling System
  • Mitochondria / metabolism
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism*
  • Protein Binding
  • RNA / metabolism
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sodium-Hydrogen Exchangers / metabolism
  • Transcription, Genetic
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases


  • Adrenergic alpha-Agonists
  • Diuretics
  • Enzyme Inhibitors
  • Interleukin-8
  • NF-kappa B
  • RNA, Messenger
  • Sodium-Hydrogen Exchangers
  • RNA
  • Lithium
  • Luciferases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Lithium Chloride