Barrier function of the epidermis is maintained by precise expression of keratinocyte-specific structural proteins to form the cornified cell envelope (CE). Loricrin, a major component of the CE, is expressed at the late stage of keratinocyte differentiation. In this study, we reveal the isoform-specific function of protein kinase C (PKC) in the regulation of loricrin expression. Both PKC delta and PKC eta have been recognized as differentiation-promoting isoforms. However, loricrin expression was inversely controlled by PKC delta and PKC eta in cultured keratinocytes and 3D skin culture; i.e. loricrin expression was decreased by PKC delta and increased by PKC eta. To clarify the mechanisms that PKC delta and PKC eta oppositely regulate the loricrin expression, we examined the expression of activator protein-1 (AP-1) family proteins, which modulate the transcription of loricrin and are downstream molecules of PKC. PKC delta decreased c-Jun expression, whereas PKC eta increased JunD, which are positive regulators of loricrin transcription. These findings suggest that inverse effects of PKC delta and PKC eta on loricrin expression attributes to the expression of c-Jun and JunD. (C) 2010 Elsevier Inc. All rights reserved.