Interleukin‐4 up‐regulation of epidermal interleukin‐19 expression in keratinocytes involves the binding of signal transducer and activator of transcription 6 (Stat6) to the imperfect Stat6 sites

Abstract

Summary Interleukin‐19 (IL‐19) plays an important role in asthma by stimulating T helper type 2 (Th2) cytokine production. Interestingly, IL‐4, a key Th2 cytokine, in turn up‐regulates IL‐19 expression in bronchial epithelial cells, so forming a positive feedback loop. In atopic dermatitis (AD), another Th2 disease closely related to asthma, IL‐19 is up‐regulated in the skin. We propose to use IL‐4 transgenic (Tg) mice and human keratinocyte culture to delineate the molecular mechanisms involved in the up‐regulation of IL‐19 in AD. IL‐19 is similarly up‐regulated in the skin of IL‐4 Tg mice as in human AD. Next we show that IL‐4 up‐regulates IL‐19 expression in keratinocytes. Interestingly, the up‐regulation was suppressed by a pan‐Janus kinase (Jak) inhibitor, suggesting that the Jak–signal transducer and activator of transcription (Jak‐STAT) pathway may be involved. Dominant negative studies further indicate that STAT6, but not other STATs, mediates the up‐regulation. Serial 5′ deletion of the IL‐19 promoter and mutagenesis studies demonstrate that IL‐4 up‐regulation of IL‐19 in keratinocytes involves two imperfect STAT6 response elements. Finally, chromatin immunoprecipitation assay studies indicate that IL‐4 increases the binding of STAT6 to its response elements in the IL‐19 promoter. Taken together, we delineate the detailed molecular pathway for IL‐4 up‐regulation of IL‐19 in keratinocytes, which may play an important role in AD pathogenesis.

Increased Interleukin-19 Expression in Cutaneous T-cell Lymphoma and Atopic Dermatitis

“…Stimulation with IL-13, IL-22, or IFN-γ did not change IL-19 mRNA expression (data not shown). Thus, IL-19 mRNA expression by human keratinocytes increased by IL-17A or IL-4 stimulation, which was consistent with previous reports (4,5,7,8).…”

“…Important cellular sources of IL-19 are thought to be monocytes (1)(2)(3), keratinocytes (4)(5)(6)(7)(8) and bronchial epithelial cells (9). IL-4 and IL-17A have been reported to induce IL-19 expression by human keratinocytes (4,5,7,8). The IL-19 receptor consists of IL-20R1 and IL-20R2 (10)(11)(12).…”

“…Many groups have documented increased IL-19 expression in the diseased skin of psoriasis in comparison with non-diseased skin of the same patients or that of healthy controls (4,5,(14)(15)(16). IL-19 is also reported to be up-regulated in lesional skin of atopic dermatitis (AD) (4,5). AD is a chronic inflammatory skin disease that affects 10-20% of children and 1-3% of adults in developed countries.…”

A molecular mechanism for IL-4 suppression of loricrin transcription in epidermal keratinocytes: implication for atopic dermatitis pathogenesis

“…34 We have shown that IL-4 regulates hundreds of genes in keratinocytes. 12,13,15,16 IL-4-activated Stat6 binds to the GAS site to regulate its target genes, 15,16 and a typical GAS site for Stat6 consists of two palindromic half sites TTC and GAA with four spacing nucleotides in between. 15 Probably because of a lack of typical Stat6 binding sites, Stat6 has never been reported to bind to the loricrin promoter.…”

“…35 Since p300/CBP is the common coactivator for both loricrin and Stat6 target genes (e.g. CCL26 and IL-19 15,16 ), IL-4 signaling in keratinocytes may lead to activated Stat6 recruiting p300/CBP, thus sequestering this coactivator from the loricrin general transcription machinery (Figure 1). IL-4 has been shown to signal through different pathways, such as Jak/Stat, NF-kB, MAPK and PI3.…”