Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that plays an important role in the regulation of skin immunity and is upregulated in the lesions of atopic dermatitis patients. Therefore, inhibitors of TSLP production are effective as therapeutic agents for atopic dermatitis. In our laboratory, we found that hypoxia condition and DMOG, a PHD inhibitor, suppressed the expression of TSLP in keratinocytes. In this study, we analyzed the mechanism by which PHD inhibitors suppress TSLP expression.
TSLP mRNA expression was induced in human keratinocyte cell line HaCaT cells by combined stimulation with TNFα, IL-4, FSL-1, and PAR2 agonist (T4FP stimulation), which was inhibited by PHD inhibitors Roxadustat and Enarodustat. The knockdown of HIF1α by siRNA abolished the inhibitory effect of Enarodustat on TSLP expression. Chromatin immunoprecipitation assay suggested that HIF1α binds to the hypoxia response elements (HRE) on the TSLP promoter.
In conclusion, this study demonstrated that PHD inhibitors suppressed TSLP mRNA expression induced by T4FP stimulation in HaCaT cells. The suppression of TSLP expression was found to be HIF1α-dependent. In addition, we found that HIF1α binds to the HRE on the TSLP promoter, suggesting that HIF1α may affect transcription by binding to the TSLP promoter.