Organotypic Modeling of Human Keratinocyte Response to Peroxisome Proliferators

Abstract

Peroxisome proliferators (PPs) are a diverse chemical group including hypolipidemic drugs and some fatty acids. Their stimulation of PP-activated receptors (PPARs) and subsequent control of gene expression regulates metabolism and differentiation in many cells. PPs have multiple opportunities to target human epidermal keratinocytes because of delivery through dietary, clinical, and/or topical exposure routes. PPAR knockout mice and PP treatment of mouse skin or human keratinocytes in monolayer culture have established some effects for PPs in cutaneous differentiation. However, incomplete epidermal maturation characteristic of monolayer keratinocytes and rodent-specific effects may limit our full understanding of human keratinocyte responses to PPs. To address these issues, we investigated PP influence on primary human keratinocytes in organotypic cultures that recapitulate biochemical markers of epidermis. We found that the PPARα agonists clofibrate, docasohexaenoic acid, and WY-14,643 produced mild to moderate keratinocyte hyperplasia, increased stratification (particularly of granular and cornified layers), and enhanced levels of the differentiation markers filaggrin, ABCA12, and phosphorylated HSP27. Several PP effects generated in the organotypic system, however, were distinct from those previously reported for rodent skin and human keratinocyte monolayer cultures, suggesting that the species and growth context of target cells can impact exposure outcomes. Given the utility of organotypic cultures for modeling the epidermis, studies in this system may bridge the gap between the rodent assays and clinical studies of human epidermal responses to PPs.