Heat-killed microorganisms induce PAI-1 expression in human peritoneal mesothelial cells: role of interleukin-1alpha.
Human peritoneal mesothelial cells (HMCs) have a critical role in maintaining the intraperitoneal balance between fibrinolysis and coagulation by expressing the fibrinolytic enzyme, tissue-type plasminogen activator (tPA), as well as a specific plasminogen activator inhibitor (type 1; PAI-1). During bacterial peritonitis, the balance between intraperitoneal generation and degradation of fibrin is disturbed. As a consequence, severe peritoneal damage occurs, which is one of the leading causes of patient dropout from continuous ambulatory peritoneal dialysis (CAPD) therapy. Cultured HMCs isolated from omental biopsy specimens were used to study the effect of heat-killed strains (2 x 10(8)/mL) of Staphylococcus aureus, Staphylococcus epidermidis, and Escherichia coli on the synthesis of tPA and PAI-1. Conditioned media were obtained by incubating cells with the different bacterial strains. tPA and PAI-1 antigen concentrations were measured in the cell supernatants by enzyme-linked immunosorbent assay. Each of the three heat-killed microorganisms induced a time-dependent increase in PAI-1 synthesis. After a 48-hour incubation period, the strongest effect was seen in the presence of S aureus (3.5-fold versus control), followed by S epidermidis (2.5-fold versus control) and E coli (1.5-fold versus control). Under the same conditions, tPA antigen levels did not change after exposure to S aureus or E coli, whereas the addition of S epidermidis resulted in enhanced tPA antigen production (2-fold versus control). The increase in PAI-1 synthesis in the presence of the heat-killed microorganisms was preceded by similar changes in interleukin-1alpha (IL-1alpha) levels. Inhibiting the activity of IL-1alpha with a neutralizing antibody significantly reduced bacterial-induced PAI-1 production. Our results indicate that the fibrinolytic imbalance during bacterial peritonitis depends on the bacterial species. The increase in PAI-1 synthesis, not the decrease in the production of tPA, alters mesothelial fibrinolytic activity. Because the increase in PAI-1 expression is significantly quenched by blocking the activity of IL-1alpha, the mesothelial release of this cytokine is involved in bacterial-induced changes in the fibrinolytic system.
Medizinische Klinik, Klinikum Innenstadt der Universität München, Munich, Germany.
S
S
Mandl-Weber
B
B
Haslinger
S R
SR
Lederer
T
T
Sitter
D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D004848:Epithelium / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology; D005342:Fibrinolysis / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D010531:Peritoneal Dialysis, Continuous Ambulatory / Q000009:adverse effects; D010537:Peritoneum / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D010538:Peritonitis / Q000209:etiology / Q000276:immunology / Q000382:microbiology; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology; D013212:Staphylococcus epidermidis / Q000276:immunology; D010959:Tissue Plasminogen Activator / Q000276:immunology / Q000378:metabolism
D001428:Bacterial Vaccines; D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator