Retinoic acid upregulates the plasminogen activator system in human epidermal keratinocytes

The activation of the proteolytic plasminogen activator system is important for the re-epithelialization of skin wounds, Keratinocytes synthesize and secrete the urokinase-type plasminogen activator, which binds to its specif ic receptor on keratinocytes, Receptor-bound urokinase-type plasminogen act ivator efficiently activates cell surface bound plasminogen. This results i n pericellular proteolysis, which facilitates keratinocyte migration. Uroki nase-type plasminogen activator activity is specifically controlled by plas minogen activator inhibitor-1 and -2. As retinoids have been reported to ac celerate epithelialization of skin wounds in animal studies and clinical se ttings, we investigated the effects of all-trans retinoic acid on the plasm inogen activator system in human epidermal keratinocytes, As tested in a ch romogenic plasminogen activation assay, incubation with 10 muM all-tuans re tinoic acid caused a marked induction of cell-associated plasminogen activi ty after 24 h, and this induction was blocked by neutralizing anti-urokinas e-type plasminogen activator antibodies, but not anti-tissue-type plasminog en activator antibodies. All-trans retinoic acid lead to a strong increase in urokinase-type plasminogen activator (enzyme-linked immunosorbent assay) and urokinase-type plasminogen activator receptor cell surface expression (flow cytometry) after 24 h. At this time-point, tissue-type plasminogen ac tivator and plasminogen activator inhibitor-1 and -2 proteins were not or o nly slightly increased. Northern blot analyses revealed that all-trans reti noic acid caused an early and short-lived increase of plasminogen activator inhibitor-1, but a prolonged induction of urokinase-type plasminogen activ ator and urokinase-type plasminogen activator receptor mRNA levels, Collect ively, these data suggest that all-tuans retinoic acid activates the plasmi nogen activator system in human epidermal keratinocytes by differentially r egulating activating and inhibiting components. The activation of the plasm inogen activator system may be one mechanism by which all-trans retinoic ac id exerts beneficial effects in cutaneous wound healing.