In the epidermis, tight junction (TJ) structure is specifically located in the stratum granulosum, where the expression of Delta Np63, a p53 family transcription factor, is attenuated. Since the relationship between Delta Np63 and barrier function has not been fully uncovered, we assessed expression profiles of TJ proteins in skin tissues and cultured keratinocytes. The results showed that expression of Delta Np63 and that of claudin-4 were inversely correlated in healthy human epidermis. In vitro studies using HaCaT keratinocytes revealed functional relevance of Delta Np63 and claudin-4. Curiously, Toll-like receptor (TLR)-3 ligand, which is known to be liberated from damaged cells, suppressed Delta Np63 expression and concomitantly up regulated claudin-4 expression in primary keratinocytes. More interestingly, a broad expression pattern of claudin-4 was found in the epidermis of atopic dermatitis (AD), a barrier defect disorder, which contains Delta Np63-lacking keratinocytes as we reported previously. Therefore, upregulation of claudin-4 expression regulated by Delta Np63 might be associated with complementary or repair responses of damaged keratinocytes with AD. (C) 2014 Elsevier Inc. All rights reserved.