Abstract
Atopic dermatitis (AD) is a common inflammatory skin disease. Recent studies have revealed the involvement of T helper (Th)2 cytokines including Interleukin 4 (IL-4) in the pathogenesis of AD. Since epidermal Langerhans cells (LCs) and dermal myeloid dendritic cells (DCs) produce CCL17 and CCL22 that chemoattract Th2 cells, interfering with CCL17 and CCL22 production from LCs and dermal myeloid DCs may be beneficial in the treatment of AD. To investigate this, we stimulated murine bone marrow-derived DCs (BMDCs) with IL-4. IL-4 stimulation produced Ccl17 and Ccl22, which was attenuated by soybean tar Glyteer, a known aryl hydrocarbon receptor (Ahr) activator. Notably, Glyteer treatment blocked the nuclear translocation of Stat6 induced by IL-4 stimulation, suggesting that this treatment impairs the IL-4/Stat6 signaling pathway in BMDCs. Unexpectedly, Glyteer treatment did not potently upregulate the expression of Cyp1a1, a specific Ahr-responsive gene, suggesting that its inhibitory machinery for Ccl17 and Ccl22 expression is likely to operate in an Ahr-independent manner. These findings indicate that Glyteer may exhibit therapeutic potential for AD by downregulating the CCL17 and CCL22 production from DCs in a Th2-deviated microenvironment.
Highlights
Atopic dermatitis (AD) is a common inflammatory skin disease
We first examined whether Interleukin 4 (IL-4) stimulation induced Ccl17 and Ccl22 production in bone marrow-derived DCs (BMDCs)
There are two published reports stating that FICZ inhibits the phosphorylation of Stat6 in naïve CD4+ T cells [28] and that coal tar inhibits the oxidative inactivation of PTPN1, a negative regulator of STAT6, and thereby attenuates the phosphorylation of Stat6 in keratinocytes [8]; whether aryl hydrocarbon receptor (Ahr) activation is involved in this has not been determined
Summary
Atopic dermatitis (AD) is a common inflammatory skin disease. Its pathogenesis is thought to be derived from cells of the adaptive immune system, mainly T helper (Th) lymphocytes [1]. Dendritic cells (DCs) play an important role in the pathogenesis of AD, since they can mediate T-cell polarization and produce proinflammatory cytokines and chemokines [3]. DCs serve as sentinels of the immune system and represent a heterogeneous family of myeloid cells. Several studies have revealed that LCs and dermal myeloid DCs produce prominent CCL17 and CCL22 in the skin of AD patients [4,5,6]. CCL17 and CCL22 are considered to be AD-related chemokines produced by skin myeloid DCs [5,6], which chemoattract Th2 cells and maintain the Th2 immune response [5]. Interfering with CCL17 and CCL22 production from LCs and dermal myeloid DCs may be beneficial in the treatment of AD
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