THROMBOMODULIN EXPRESSION BY HUMAN KERATINOCYTES INDUCTION OF COFACTOR ACTIVITY DURING EPIDERMAL DIFFERENTIATION

Thrombomodulin is an endothelial cell surface glycoprotein that inhibi ts the procoagulant activities of thrombin and accelerates activation of the anticoagulant protein C. Because protein C deficiency is associ ated with cutaneous thrombosis, we investigated the expression of thro mbomodulin in human skin. Thrombomodulin was detected by immunohistoch emical staining both in dermal endothelial cells and in epidermal kera tinocytes. Within the epidermis, thrombomodulin staining was limited t o keratinocytes of the spinous layer, suggesting that thrombomodulin i s induced when basal keratinocytes begin to terminally differentiate. Thrombomodulin expression also correlated with squamous differentiatio n in epidermal malignancies; little or no thrombomodulin staining was seen in five basal cell carcinomas, whereas strong thrombomodulin stai ning was observed in each of five squamous cell carcinomas. Human fore skin keratinocytes cultured in medium containing 0.07 mM calcium chlor ide synthesized functional thrombomodulin with cofactor activity compa rable to thrombomodulin in human umbilical vein endothelial cells. Sti mulation of keratinocyte differentiation with 1.4 mM calcium chloride for 48 h produced 3.5-, 3.2-, and 5.6-fold increases in thrombomodulin cofactor activity, antigen, and mRNA, respectively. These observation s suggest that thrombin is regulated by keratinocyte thrombomodulin at sites of cutaneous injury, and indicate a potential role for thrombom odulin in epidermal differentiation.