REGULATION OF THROMBOMODULIN EXPRESSION BY ALL-TRANS-RETINOIC ACID AND TUMOR-NECROSIS-FACTOR-ALPHA - DIFFERENTIAL RESPONSES IN KERATINOCYTES AND ENDOTHELIAL-CELLS

Thrombomodulin is a cell-surface anticoagulant glycoprotein expressed by vascular endothelial cells and epidermal keratinocytes. Thrombomodu lin expression in endothelial cells is regulated by retinoic acid and tumor necrosis factor-alpha (TNF), agents that also modulate epidermal differentiation, We examined thrombomodulin function and regulation o f thrombomodulin expression by all-trans retinoic acid (ATRA) and TNF in human keratinocytes and endothelial cells, Untreated keratinocytes and endothelial cells expressed thrombomodulin of comparable activity and apparent thrombin affinity. Incubation of keratinocytes with 10 mu mol/L ATRA for 24 hours increased thrombomodulin activity 5.4 +/- 0.9 -fold (mean +/- SE), with equivalent increases observed in thrombomodu lin protein (5.5 +/- 2.1-fold) and mRNA (4.2 +/- 1.2-fold). Incubation of keratinocytes with 1.0 nmol/L TNF markedly increased expression of keratinocyte transglutaminase, but had no effect on thrombomodulin ac tivity, protein, or mRNA. In endothelial cells, ATRA produced a small increase in thrombomodulin activity (1.9 +/- 0.1-fold), and incubation with TNF for 24 hours decreased thrombomodulin activity 83% +/- 7%, T he activity profile of keratinocyte thrombomodulin exhibited a distinc t maximum near 1.0 mmol/L Ca2+, These results demonstrate that keratin ocyte thrombomodulin is regulated by retinoids and Ca2+, but not by TN F, and that regulation of thrombomodulin expression differs in keratin ocytes and endothelial cells. (C) 1996 by The American Society of Hema tology.