Abstract
Keratinocytes were shown to induce the activation of plasminogen activator resulting in the formation of plasmin and the initiation of proteolysis in vitro. Activation of surface bound plasminogen may localize protease activity in the pericellular microenvironment and play a role in inducing both a conformational change and cell locomotion. Plasmin, however, can induce non-proteolytic effects on certain cell functions in a variety of cell lineages. In the present study we examined the effects of plasmin on keratinocytes with a focus on its role in the process of re-epithelialization, which included studies of cell migration, phagocytic-killing and cell proliferation. Migration of freshly isolated human epidermal keratinocytes was analyzed utilizing the agarose gel assay in the presence of 10% human serum. Plasmin at the concentration of 25 U/l induced a 160% increase in the chemotactic migration of keratinocytes that was completely blocked by the plasmin inhibitor α2-antiplasmin (Serpin). In the absence of serum, plasmin also induced a reversible chemotactic migration of HaCaT keratinocytes as determined utilizing the microchemotaxis assay. Dose-response analysis showed a bi-phasic effect of plasmin with a maximum increase of 52% in keratinocyte chemotaxis at a concentration of 25 U/l. HaCaT cells on the other hand, showed no detectable in vitro chemokinesis by plasmin. Phagocytic-killing of Candida albicans by freshly isolated epidermal keratinocytes was enhanced in the presence of 25 U/l plasmin which was also reversible by the addition of Serpin. Spontaneous proliferation of HaCaT keratinocytes as determined by 3H-Thymidine uptake on the other hand, was reduced by 47 and 13% in cultures with 25 U/l plasmin for 24 and 48 h respectively, in a Serpin reversible manner. These data suggest that plasmin-induced chemotactic migration of epidermal keratinocytes is accompanied by enhanced phagocytic-killing coupled with suppression of proliferation of these cells which may facilitate re-epithelialization following skin injury.
Highlights
The plasminogen/plasmin system has been found to play a modulatory role in many physiological and pathophysiological processes of various cell lineages (Plow and Miles, 1990; Lijnen, 1996)
Plasmin at the concentration of 25 U/l significantly enhanced the migration activity of keratinocytes compared to spontaneous migration (Fig. 2)
Evaluation of cell migration by the measurement of the distance that keratinocytes traveled during the incubation period revealed a mean value of a 1.6-fold increase in response to plasmin as compared to medium alone
Summary
The plasminogen/plasmin system has been found to play a modulatory role in many physiological and pathophysiological processes of various cell lineages (Plow and Miles, 1990; Lijnen, 1996). Activation of membrane bound plasminogen may localize protease activity to the pericellular micro-environment (Blasi, 1993; Boxman et al, 1995; Bechtel et al, 1996; Chen and Jensen, 1996; Rox et al, 1996). Plasmin activation has been reported to lead to an increase in cell mobility or spreading through enzymatic release of cell contacts, and play a role in certain physiological and pathological processes including wound healing, tumor cell invasion or embryonic development (Grondahl-Hansen et al, 1988; Stephens et al, 1989; Baird et al, 1990; Del Rosso et al, 1990; Meissauer et al, 1992; Blasi, 1993; Reinartz et al, 1994; Bechtel et al, 1996)
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