Activation of Aryl Hydrocarbon Receptor Negatively Regulates Thymic Stromal Lymphopoietin Gene Expression via Protein Kinase Cδ-p300–NF-κB Pathway in Keratinocytes under Inflammatory Conditions

Abstract

Epithelial-derived thymic stromal lymphopoietin (TSLP) plays an important role in pathogenesis in several types of dermatitis. Recently, the anti-inflammatory effects of aryl hydrocarbon receptor (AhR) have been reported in inflamed skin. In this study, keratinocytes were stimulated with tumor necrosis factor-α or flagellin in combination with AhR ligands or antagonist. TSLP gene expression and recruitment of transcriptional regulator to TSLP gene promoter were determined. The effects of AhR activation were also studied in DNFB-induced dermatitis model. We found that AhR activation suppressed upregulation of TSLP expression in keratinocytes treated with tumor necrosis factor-α or flagellin. In addition, AhR activation induced protein kinase Cδ-mediated phosphorylation of p300 at serine 89, leading to decreased acetylation and DNA binding activity of NF-κB p65 to the TSLP gene promoter. We also found that AhR activation alleviates dermatitis induced by DNFB treatment. Protein kinase Cδ depletion by small interfering RNA abolished the beneficial effect of AhR activation on dermatitis. Our study suggests that AhR activation may help to reduce inflammation in the dermatitis via downregulation of TSLP expression.