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Lithium regulates keratinocyte proliferation via glycogen synthase kinase 3 and NFAT2 (nuclear factor of activated T cells 2)
Author(s) -
Hampton Philip J.,
Jans Ralph,
Flockhart Ross J.,
Parker Graeme,
Reynolds Nick J.
Publication year - 2012
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22872
Subject(s) - gsk 3 , glycogen synthase , microbiology and biotechnology , chemistry , gsk3b , lithium (medication) , keratinocyte , kinase , biochemistry , enzyme , biology , endocrinology , in vitro
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. J. Cell. Physiol. 227: 1529–1537, 2012. © 2011 Wiley Periodicals, Inc.