title: Lithium regulates keratinocyte proliferation via glycogen synthase kinase 3 and NFAT2 (nuclear factor of activated T cells 2).
abstract: Certain environmental factors including drugs exacerbate or precipitate psoriasis. Lithium is the commonest cause of drug-induced psoriasis but underlying mechanisms are currently unknown. Lithium inhibits glycogen synthase kinase 3 (GSK-3). As lithium does not exacerbate other T-cell-mediated chronic inflammatory diseases, we investigated whether lithium may be acting directly on epidermal keratinocytes by inhibiting GSK-3. We report that lithium-induced keratinocyte proliferation at therapeutically relevant doses (1-2 mM) and increased the proportion of cells in S phase of the cell cycle. 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. Nuclear factor of activated T cells (NFAT) is an important substrate for GSK-3 and for cyclosporin, an effective treatment for psoriasis that inhibits NFAT activation in keratinocytes as well as in lymphocytes. 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. Taken together, these data identify GSK-3 and NFAT2 as key regulators of keratinocyte proliferation and as potential molecular targets relevant to lithium-provoked psoriasis.
authors.affiliation: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hampton
authors.forename: Ralph
authors.initials: R
authors.lastname: Jans
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Flockhart
authors.forename: Graeme
authors.initials: G
authors.lastname: Parker
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Reynolds
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008094:Lithium / Q000633:toxicity*; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011565:Psoriasis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D034741:RNA, Small Interfering; D008094:Lithium; D038362:Glycogen Synthase Kinase 3