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

Lithium has been documented to regulate apoptosis and apoptotic gene expression via NF-κB and mitogen-activated protein (MAP) kinase-dependent mechanisms. Since both NF-κB and MAP kinases are also important mediators of inflammatory gene expression, we investigated the effect of lithium on NF-κB- and MAP kinase-mediated inflammatory gene expression. Incubation of human intestinal epithelial cells with lithium induced both enhanced NF-κB DNA binding and NF-κB-dependent transcriptional activity. In addition, lithium stimulated activation of both the p38 and p42/44 MAP kinases. This lithium-induced up-regulation of NF-κB 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-κB and MAP kinase activation.