1. ¹Department of Dermatology, Aarhus University Hospital, Aarhus University, Aarhus, Denmark
2. ²Department of Clinical Genetics, Aarhus University Hospital and Institute of Human Genetics, Aarhus University, Aarhus, Denmark
3. ³Discovery, Novo Nordisk A/S, Bagsvaerd, Denmark

Correspondence: Dr Lars Iversen, Department of Dermatology, Aarhus University Hospital, P.P. Orumsgade 11, DK-8000 Aarhus C, Denmark. E-mail: larsiversen@dadlnet.dk

Received 21 September 2006; Revised 13 November 2006; Accepted 15 November 2006; Published online 25 January 2007.

Abstract

IL-20 is a novel member of the IL-10 cytokine family with pleiotropic effects. Current knowledge of what triggers and regulates IL-20 gene expression is sparse. The aim of this study was to investigate the regulation of IL-20 expression in cultured normal human keratinocytes. The expression of IL-20 was rapidly induced by proinflammatory stimuli, in particular IL-1, IL-6, and UVB irradiation. Using kinase inhibitors and small-interfering RNA, we discovered that the p38 mitogen-activated protein kinase (MAPK) as well as inhibitory B kinase -NF-B signaling pathways are crucial for IL-20 expression. By electrophoretic mobility shift assay two B-binding sites were identified upstream from the start codon in the IL-20 gene. Supershift analysis revealed binding of the p50/p65 heterodimer. Furthermore, the p38 MAPK was shown to exert its effects on IL-20 expression through activation of the downstream kinase mitogen- and stress-activated kinase 1 (MSK1), indicating transactivation of NF-B driven IL-20 messenger RNA transcription as an important mechanism of action. IL-20 is assumed to be a key cytokine in the pathogenesis of psoriasis and possibly cancer, and therefore the p38 MAPK, MSK1, and NF-B may be important new molecular targets for the modulation of IL-20 expression in these diseases.