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We Investigated the effects of a number of stimulatory agents on the production of both cell-associated and extracellular elastase-type enzymes on human monocytemacrophages In vitro and of the modulation of such effects by modification of cellular cholesterol content The stimulatory agents included phorbol myristate acetate (PMA) and the Inflammatory mediators, llpopolysaccharide (LPS), opsonlzed zymosan (OZ), and platelet activating factor (PAF). Using the synthetic substrate, N-succinyl-trialanyl-paranrtroanlllde (SANA), we detected cell-associated elastase- Ilke activity In monocyte-derived macrophages. Such activity Increased markedly with cell maturation over the period from 5 to 15 days of adherence culture. While PAF (10 μg/ml) and LPS (10 μg/ml) were without effect on cell-associated elastase-llke activity in macrophages, PMA (100 ng/ml) and OZ (1 mg/ml) markedly stimulated such activity In cells cultured for 15 days. Furthermore, a fivefold increase In the cell-associated elastase-llke activity of macrophages occurred upon cholesterol loading of the cells with acetytated low density llpoprotein (AcLDL). By contrast, this activity was markedly diminished upon depletion of cellular cholesterol content after Incubation with high density llpoprotein (HDLj). Latent elastlnolytic activity In the culture medium was detected by use of a radioactive substrate, Insoluble 3H-etastln, after Initial trypttc treatment of the medium. Such latent elastase activity was secreted only by activated macrophages; the relative potency of stimulation was: PMA>LPS=PAF>OZ. Increase In cellular cholesterol content alone markedly enhanced the secretion of elastase (from undetectable levels to 28 ng of 3H-etastln degraded/hr/pg DNA). In all cases, both the ceJI-associatad and secreted latent elastlnoryttc activities were due to metalloproteeses, in view of their 90% Inhibition by 2 mM EOTA. Cholesterol-loaded macrophages, which displayed an approximately 40-fold Increase in total cholesterol content as compared to control cells, remained sensitive to the action of activators of OZ and PMA, while LPS and PAF exerted only weak effects. Our data Indicate that cellular cholesterol content and Inflammatory mediators are effective stimulants of the production and secretion of elastase-type enzymes by human monocyte-macrophages. Among these factors, cellular cholesterol content, OZ, PAF, and LPS may represent factors of relevance to the Inflammatory role of the macrophage in atherogenesls and more specifically to the alteration of elastln structure In the extracellular matrix of the vessel wall.
Arteriosclerosis – Wolters Kluwer Health
Published: Mar 1, 1990
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