IL-20 gene expression is induced by IL-1beta through mitogen-activated protein kinase and NF-kappaB-dependent mechanisms.
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.
Otkjaer
Kristian
K
Department of Dermatology, Aarhus University Hospital, Aarhus University, Aarhus, Denmark.
Kragballe
Knud
K
Johansen
Claus
C
Funding
Anne T
AT
Just
Helle
H
Jensen
Uffe B
UB
Sørensen
Lotte G
LG
Nørby
Peder L
PL
Clausen
Jes T
JT
Iversen
Lars
L
D000328:Adult; D002478:Cells, Cultured; D019281:Dimerization; D000078404:Epidermal Cells; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D053582:Interleukin-1alpha / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D052002:NF-kappa B p50 Subunit / Q000737:chemistry / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D051996:Transcription Factor RelA / Q000737:chemistry / Q000378:metabolism*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D015850:Interleukin-6; D007378:Interleukins; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D051996:Transcription Factor RelA; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C116919:mitogen and stress-activated protein kinase 1; C482625:MAP3K3 protein, human; C422042:interleukin 20