Original Article

Subject Category: Cell Biology

Journal of Investigative Dermatology (2007) 127, 1326–1336. doi:10.1038/sj.jid.5700713; published online 25 January 2007

IL-20 Gene Expression Is Induced by IL-1bold italic beta through Mitogen-Activated Protein Kinase and NF-kappaB-Dependent Mechanisms

Kristian Otkjaer1, Knud Kragballe1, Claus Johansen1, Anne T Funding1, Helle Just1, Uffe B Jensen2, Lotte G Sørensen3, Peder L Nørby3, Jes T Clausen3 and Lars Iversen1

  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.

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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-1beta, 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 kappaB kinase -NF-kappaB signaling pathways are crucial for IL-20 expression. By electrophoretic mobility shift assay two kappaB-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-kappaB 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-kappaB may be important new molecular targets for the modulation of IL-20 expression in these diseases.

Abbreviations:

ATF, activating transcription factor 1; CREB, cAMP response element-binding protein; EMSA, electrophoretic mobility shift assay; IKK, inhibitory kappaB-kinase; mRNA, messenger RNA; MAPK, mitogen-activated protein kinase; MEKK3, MAPK kinase kinase 3; MSK1, mitogen- and stress-activated kinase 1; NHEK, normal human epidermal keratinocytes; siRNA, small-interfering RNA; TAK1, transforming growth factor-beta-activated kinase

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