Abstract
Atopic dermatitis (AD), a chronic, pruritic, inflammatory skin disease, is histopathologically characterized by epidermal hyperplasia and infiltration of T cells, mast cells, and eosinophils. Clinical study and basic research have established that IL-4 plays an important role in the pathogenesis of AD. In this report, using HaCat cells, we show that CCL26, a chemokine for eosinophils, is up-regulated by IL-4 at both the mRNA and protein levels. IL-4 also enhances CCL26 promoter activity. Serial 5' deletion of the promoter and mutagenesis study reveal that the proximal Stat site is the key response element for IL-4 regulation of CCL26. Although IL-4 increases phosphorylation of both Stat3 and Stat6, it only activates Stat6 as shown by dominant negative studies. In addition, we found that IL-4 induces Stat6 nuclear translocation and stimulates phosphorylation of Jak1 and Jak2 but not Tyk2. IL-4 up-regulation of CCL26 can be suppressed by Jak inhibitors in a dose-dependent manner. Taken together, results of this investigation reveal that IL-4 signals through the Jak1, 2/Stat6 pathway in keratinocytes to stimulate CCL26 expression and this may provide an explanation for the pathogenesis of AD.
Published by Elsevier Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Blotting, Western
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Cell Line
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Chemokine CCL26
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Chemokines, CC / genetics
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Chemokines, CC / metabolism*
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Dermatitis, Atopic / genetics
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Dermatitis, Atopic / metabolism
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Dermatitis, Atopic / pathology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Gene Expression / drug effects
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Humans
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Immunohistochemistry
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Interleukin-4 / pharmacology*
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Interleukin-4 / physiology
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Janus Kinase 1 / antagonists & inhibitors
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Janus Kinase 1 / metabolism*
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Janus Kinase 2 / antagonists & inhibitors
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Janus Kinase 2 / metabolism*
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Keratinocytes / cytology
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Keratinocytes / drug effects*
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Keratinocytes / metabolism
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Luciferases / genetics
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Luciferases / metabolism
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Phosphorylation / drug effects
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Promoter Regions, Genetic / genetics
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Response Elements / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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STAT6 Transcription Factor / metabolism*
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Signal Transduction / drug effects
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Tyrphostins / pharmacology
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Up-Regulation / drug effects
Substances
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CCL26 protein, human
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Chemokine CCL26
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Chemokines, CC
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Enzyme Inhibitors
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STAT6 Transcription Factor
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STAT6 protein, human
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Tyrphostins
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alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
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Interleukin-4
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Luciferases
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JAK1 protein, human
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JAK2 protein, human
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Janus Kinase 1
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Janus Kinase 2