Aldo-Keto Reductase 1C3 Is Expressed in Differentiated Human Epidermis, Affects Keratinocyte Differentiation, and Is Upregulated in Atopic Dermatitis

Aldo-keto reductase 1C3 (AKR1C3) has been shown to mediate the metabolism of sex hormones and prostaglandin D-2 (PGD(2)), a lipid mediator that promotes skin inflammation in atopic dermatitis (AD). As both have a role in skin function and pathology, we first sought to investigate the expression pattern of AKR1C3 in normal human epidermis. Immunofluorescence revealed a strong expression of AKR1C3 in the differentiated suprabasal layers compared with the basal layer. Western blot analysis and quantitative PCR confirmed that AKR1C3 expression was also upregulated in differentiation-induced primary human keratinocytes (PHKs). To investigate the functional role of AKR1C3 during PHK differentiation, its expression and activity (measured as PGD(2) reduction to 9 alpha,11 beta-PGF(2) by ELISA) were impaired by small interfering RNA or 2'-hydroxyflavanone, respectively. Cytokeratin 10 (K10) and loricrin expression were then examined by western blot analysis, thus revealing altered expression of these differentiation markers. Finally, following an observation that the AD-associated mediator, PGD(2), upregulated AKR1C3 expression in PHKs, we used immunofluorescence to examine AKR1C3 expression in AD and psoriasis lesions. AKR1C3 was found to be upregulated in AD but not in psoriasis lesions compared with non-lesional skin. Our work demonstrates a function for AKR1C3 in differentiation-associated gene regulation and also suggests a role in supporting inflammation in AD.