title: Upregulation of cell-surface-associated plasminogen activation in cultured keratinocytes by interleukin-1 beta and tumor necrosis factor-alpha.
abstract: 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-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-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-1 beta and TNF-alpha 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.
authors.affiliation: Laboratory for Immunopathology, University Institute for Immunology, Heidelberg, Germany.
authors.forename: M J
authors.initials: MJ
authors.lastname: Bechtel
authors.forename: J
authors.initials: J
authors.lastname: Reinartz
authors.forename: J M
authors.initials: JM
authors.lastname: Rox
authors.forename: S
authors.initials: S
authors.lastname: Inndorf
authors.forename: B M
authors.initials: BM
authors.lastname: Schaefer
authors.forename: M D
authors.initials: MD
authors.lastname: Kramer
mesh_terms: D002448:Cell Adhesion; D002460:Cell Line; D002470:Cell Survival; D003513:Cycloheximide / Q000494:pharmacology; D000078404:Epidermal Cells; D005341:Fibrinolysin / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015603:Keratinocytes / Q000378:metabolism*; D010960:Plasminogen Activators / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000032:analysis; D055293:Receptors, Urokinase Plasminogen Activator; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D007375:Interleukin-1; C524898:PLAUR protein, human; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; D010960:Plasminogen Activators; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator