Abstract
IL-22 induces STAT3 phosphorylation and mediates psoriasis-related gene expression. However, the signaling mechanism leading from pSTAT3 to the expression of these genes remains unclear. We focused on Bcl-3, which is induced by STAT3 activation and mediates gene expression. In cultured human epidermal keratinocytes, IL-22 increased Bcl-3, which was translocated to the nucleus with p50 via STAT3 activation. The increases in CXCL8, S100As and human β-defensin 2 mRNA expression caused by IL-22 were abolished by siRNA against Bcl-3. Although CCL20 expression was also augmented by IL-22, the knockdown of Bcl-3 increased its level. Moreover, the combination of IL-22 and IL-17A enhanced Bcl-3 production, IL-22-induced gene expression, and the expression of other psoriasis-related genes, including those encoding IL-17C, IL-19, and IL-36γ. The expression of these genes (except for CCL20) was also suppressed by the knockdown of Bcl-3. Bcl-3 overexpression induced CXCL8 and HBD2 expression but not S100As expression. We also compared Bcl-3 expression between psoriatic skin lesions and normal skin. Immunostaining revealed strong signals for Bcl-3 and p50 in the nucleus of epidermal keratinocytes from psoriatic skin. The IL-22-STAT3-Bcl-3 pathway may be important in the pathogenesis of psoriasis.
Keywords:
Bcl-3; IL-22; Psoriasis; STAT3; p50.
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / physiology
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B-Cell Lymphoma 3 Protein
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Cells, Cultured
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Chemokine CCL20 / biosynthesis
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Enzyme Activation
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Gene Expression Regulation / genetics*
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Humans
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Interleukin-1 / biosynthesis
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Interleukin-17 / biosynthesis
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Interleukin-17 / metabolism
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Interleukin-22
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Interleukin-8 / biosynthesis
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Interleukin-8 / genetics
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Interleukins / biosynthesis
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Interleukins / metabolism*
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Keratinocytes / metabolism
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NF-kappa B p50 Subunit / metabolism
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Phosphorylation
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics*
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Psoriasis / genetics
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Psoriasis / pathology*
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RNA Interference
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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S100 Proteins / genetics
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STAT3 Transcription Factor / metabolism*
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Skin / pathology*
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Transcription Factors / biosynthesis
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Transcription Factors / genetics*
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beta-Defensins / biosynthesis
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beta-Defensins / genetics
Substances
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B-Cell Lymphoma 3 Protein
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BCL3 protein, human
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CCL20 protein, human
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CXCL8 protein, human
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Chemokine CCL20
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DEFB4A protein, human
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IL17A protein, human
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IL17C protein, human
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IL19 protein, human
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IL36G protein, human
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Interleukin-1
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Interleukin-17
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Interleukin-8
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Interleukins
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NF-kappa B p50 Subunit
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Proto-Oncogene Proteins
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RNA, Messenger
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RNA, Small Interfering
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S100 Proteins
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S100A1 protein
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STAT3 Transcription Factor
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STAT3 protein, human
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Transcription Factors
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beta-Defensins