UP-REGULATION OF CELL-SURFACE-ASSOCIATED PLASMINOGEN ACTIVATION IN CULTURED KERATINOCYTES BY INTERLEUKIN-1-BETA AND TUMOR-NECROSIS-FACTOR-ALPHA

Keratinocytes synthesize and secrete urokinase-type plasminogen activa tor (uPA) which is bound in an autocrine manner to a specific receptor (uPA-R) at the keratinocyte surface, Plasminogen that is also bound t o specific membrane binding sites is readily activated by uPA-R-bound uPA. Thus, plasmin is provided for proteolysis of pericellular glycopr oteins. The expression of uPA and the uPA-R is confined to migrating k eratinocytes during epidermal wound healing, rather than to keratinocy tes of the normal epidermis. The regulatory factors of uPA/uPA-R expre ssion in keratinocytes remained largely elusive, Proinflammatory cytok ines, such as tumor necrosis factor-alpha (TNF-alpha) Or interleukin-1 beta (IL-1 beta), are present in epidermal wounds. We have therefore tested IL-1 beta and TNF-alpha for their influence on surface-associat ed plasminogen activation in a human keratinocyte cell line (HaCaT) as well as in primary cultures of normal human epidermal keratinocytes. Both cytokines induced the secretion of uPA into the culture supernata nts and a concomitant increase in uPA activity as well as in uPA and u PA-R antigen at the cell surface. The increase was preceded by an incr ease in specific mRNA. The induction was accompanied by an accelerated uPA-dependent and plasmin-mediated detachment of HaCaT cells from the culture substratum. Taken together, the proinflammatory cytokines IL- 1 beta and TNF-alpha induced a coordinated increase in uPA and uPA-R a s well as increased pericellular plasmin-mediated proteolysis in human epidermal keratinocytes, This function might be an element of the mol ecular cell biological events during epidermal wound healing. (C) 1996 Academic Press, Inc.