Abstract
Vitiligo is an acquired depigmentation disorder largely caused by defective melanocyte- or autoimmunity-induced melanocyte destruction. The aryl hydrocarbon receptor (AHR) is essential for melanocyte homeostasis and immune process, and abnormal AHR was observed in vitiligo. We previously identified the T allele of AHR −129C > T variant as a protective factor against vitiligo. However, biological characterization underlying such effects is not fully certain, further validation by mechanistic research is warranted and was conducted in the present study. We showed that −129T allele promoted AHR transcriptional activity through facilitating its interaction with SP1 transcription factor (SP1) compared with −129C allele. We subsequently found reduced peripheral AHR and SP1 transcript expressions in vitiligo and a negative correlation of AHR level with disease duration. We also investigated AHR-related cytokines and observed increased serum TNF-α concentration and diminished serum levels of IL-10 and TGF-β1 in vitiligo. Further genetic analysis showed that -129T carriers possessed higher levels of AHR and IL-10 than −129C carriers. Therefore, our study indicates that the modulation of AHR transcription by a promoter variant has a profound influence on vitiligo, not only advancing our understanding on AHR function but also providing novel insight into the pathogenesis of degenerative or autoimmune diseases including vitiligo.
Highlights
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and belongs to the basic-helix-loop-helix family[10]
In consideration of the critical role of AHR in both melanocyte and cellular immunity and aberrant AHR pathway in vitiligo, we previously evaluated the potential association between AHR polymorphisms and vitiligo susceptibility
As the − 129C > T polymorphism is in the core promoter region of AHR gene and is juxtaposed 5′ to the SP1 recognition sequence, we hypothesized that the AHR − 129C > T polymorphism could influence its transcription and downstream effectors in melanocyte biology or immune system, which could further affect the development of vitiligo
Summary
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and belongs to the basic-helix-loop-helix family[10]. Significantly declined expressions of AHR and its target genes were observed in the epidermis of vitiligo patients[16]. These data imply that mutation or dysfunction of AHR might be involved in vitiligo. The promoter of human AHR gene lacks TATA and CCAAT boxes but possesses several putative SP1 transcription factor (SP1) binding sites within a highly GC-rich region[18]. As the − 129C > T polymorphism is in the core promoter region of AHR gene and is juxtaposed 5′ to the SP1 recognition sequence, we hypothesized that the AHR − 129C > T polymorphism could influence its transcription and downstream effectors in melanocyte biology or immune system, which could further affect the development of vitiligo. We performed functional research to explore the molecular mechanisms underlying such genetic marker for vitiligo
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