Upregulation of Cell-Surface-Associated Plasminogen Activation in Cultured Keratinocytes by Interleukin-1βand Tumor Necrosis Factor-α

• Published in: Experimental cell research Vol. 223; no. 2; pp. 395 - 404
• Main Authors: Bechtel, Michael J., Reinartz, Jeannette, Rox, Jutta M., Inndorf, Stefan, Schaefer, Birgit M., Kramer, Michael D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.03.1996
• Subjects: Cell Adhesion; Cell Line; Cell Survival; Cycloheximide - pharmacology; Epidermis - cytology; Fibrinolysin - pharmacology; Gene Expression - drug effects; Humans; Interleukin-1 - pharmacology; Keratinocytes - metabolism; Plasminogen Activators - metabolism; Protein Synthesis Inhibitors - pharmacology; Receptors, Cell Surface - analysis; Receptors, Urokinase Plasminogen Activator; RNA, Messenger - biosynthesis; Tumor Necrosis Factor-alpha - pharmacology; Up-Regulation; Urokinase-Type Plasminogen Activator - biosynthesis; Urokinase-Type Plasminogen Activator - genetics
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1006/excr.1996.0094

Keratinocytes synthesize and secrete urokinase-type plasminogen activator (uPA) which is bound in an autocrine manner to a specific receptor (uPA-R) at the keratinocyte surface. Plasminogen that is also bound to specific membrane binding sites is readily activated by uPA-R-bound uPA. Thus, plasmin is provided for proteolysis of pericellular glycoproteins. The expression of uPA and the uPA-R is confined to migrating keratinocytes during epidermal wound healing, rather than to keratinocytes of the normal epidermis. The regulatory factors of uPA/uPA-R expression in keratinocytes remained largely elusive. Proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β), are present in epidermal wounds. We have therefore tested IL-1β and TNF-α for their influence on surface-associated 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 supernatants and a concomitant increase in uPA activity as well as in uPA and uPA-R antigen at the cell surface. The increase was preceded by an increase 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-1β and TNF-α induced a coordinated increase in uPA and uPA-R as well as increased pericellular plasmin-mediated proteolysis in human epidermal keratinocytes. This function might be an element of the molecular cell biological events during epidermal wound healing.