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.
Highlights
Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by T cells, eosinophils and mast cells infiltrating the skin
Materials IL-4, cell culture medium DMEM with or without phenol red, fetal bovine serum (FBS), charcoal stripped FBS, Penicillin/Streptomycin, nonessential amino acids, sodium pyruvate, the reverse transcriptase (RT) kit, SYBR Green PCR Master Mix, and Trizol reagent were obtained from Invitrogen (Carlsbad, CA); IRDye Secondary Antibodies, Blocking Buffers, Stripping Buffers, and PVDF membranes were from Li-Cor (Lincoln, NE); trypsin-EDTA was purchased from Mediatech (Herndon, VA); RIPA buffer, protease inhibitor cocktail, and sodium orthovanadate were purchased from Sigma
Cells were treated with different doses of IL-4 for 24 hours, and CCL26 mRNA expression was examined by real-time RT-PCR
Summary
Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by T cells, eosinophils and mast cells infiltrating the skin. More than 50% of AD patients eventually develop other atopic disorders, such as asthma and allergic rhinitis (Kapoor et al, 2008). Acute and chronic AD skin lesions have more IL-4 expressing cells than the unaffected skin of AD patients or skin samples from healthy people (Ou and Leung, 2005). IL-4 was shown to decrease the expression of human beta defensin, a potent antimicrobial peptide (AMP), leading to recurrent skin bacterial infection (Howell et al, 2006). The transgenic (Tg) mice spontaneously develop skin lesions satisfying the clinical and histological diagnostic criteria for human AD (Chen et al, 2006a)
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