Lithium regulates keratinocyte proliferation via glycogen synthase kinase 3 and NFAT2 (nuclear factor of activated T cells 2).
Bottom Line: Inhibition of GSK-3 in keratinocytes by retroviral transduction of GSK-binding protein (an endogenous inhibitory protein) or through a highly selective pharmacological inhibitor also resulted in increased keratinocyte proliferation.Both lithium and genetic/pharmacological inhibition of GSK-3 resulted in increased nuclear localization of NFAT2 (NFATc1) and increased NFAT transcriptional activation.Finally, retroviral transduction of NFAT2 increased keratinocyte proliferation whereas siRNA-mediated knockdown of NFAT2 reduced keratinocyte proliferation and decreased epidermal thickness in an organotypic skin equivalent model.
Affiliation: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.Show MeSH
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Mentions: Lithium at 1 or 2 mM induced increased proliferation of primary human keratinocytes (Fig. 1A), as measured by SRB assay maximal at 7 days. Stimulation of primary human keratinocyte growth appeared maximal at 1–2 mM lithium (Fig. 1A), consistent with the therapeutic range for lithium in patients treated for bipolar disorder of 0.4–1.2 mM (1 mM, P < 0.05, 2 mM P = 0.05, ANOVA, four independent experiments). The activity of GSK-3 is inhibited by N-terminal phosphorylation. Western analysis using an antibody specific to GSK-3β phosphorylated at N-terminal serine 9 showed that lithium (2, 5, or 10 mM lithium for 7 days) induced N-terminal phosphorylation in human keratinocytes (Fig. 1B) but did not increase total GSK-3. Keratinocytes treated with 1, 2, and 5 mM lithium were assessed by flow cytometry and an increase in the percentage of cells in S phase was seen with 2 mM lithium (Fig. 1C) and 5 mM lithium (data not shown) at 7 days. These data show that lithium promotes keratinocyte proliferation at therapeutic doses.
Affiliation: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.