Nephrol Dial Transplant (2003) 18: 1741-1747
© 2003 European Renal Association-European Dialysis and Transplant Association
TNF-
renders human peritoneal mesothelial cells sensitive to anti-Fas antibody-induced apoptosis
1 Division of Nephrology, Department of Medicine, 2 Department of Medical Research and Education, 3 Division of Ultrastructural and Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, 4 Institute of Clinical Medicine, School of Medicine, National Yang-Ming University and 5 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
Correspondence and offprint requests to: Dr An-Hang Yang, Division of Ultrastructural and Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei, Taiwan 112. Email: jychen{at}vghtpe.gov.tw
Background. Fas-mediated apoptosis is important in the regulation of immune response. Human peritoneal mesothelial cells (HPMCs) are able to regulate peritoneal inflammation, but the role of Fas in HPMCs is not clear. This study addresses the mechanisms of Fas-mediated apoptosis in HPMCs.
Methods. Tumour necrosis factor-
(TNF-) primed HPMCs were stimulated with agonistic anti-Fas antibody. The expression of Fas was evaluated by real-time reverse transcription polymerase chain reaction (TaqMan quantitative polymerase chain reaction) and flow cytometry. Apoptosis was assessed by nuclear morphology, TUNEL assay, fractional DNA content and cytokeratin 18 cleavage. Caspase activation and bcl-2 expression were analysed by western blotting. The phagocytosis of apoptotic HPMCs was demonstrated by immunofluorescence and transmission electron microscopy.
Results. Cultured HPMCs constitutively expressed Fas, and the Fas expression was upregulated by TNF-. TNF- primed HPMCs underwent apoptosis after anti-Fas antibody treatment, and the apoptotic HPMCs could be phagocytosed by macrophages. TNF- was able to downregulate bcl-2 expression. Activation of caspase-3 and caspase-8 was noted during the apoptotic process. The inhibitors of either caspase-3 or caspase-8 could prevent the Fas-induced apoptosis in HPMCs. We also detected increased HPMC apoptosis in dialysate effluent during the recovery phase of peritonitis in peritoneal dialysis patients.
Conclusions. TNF- directs HPMCs to commit apoptosis via the Fas/Fas ligand pathway through a modulation of Fas and bcl-2. Our study shows that HPMCs undergo apoptosis during peritonitis and suggests that the apoptosis of HPMCs may be related to the resolution of peritoneal inflammation.
Keywords: apoptosis; caspase; Fas; mesothelial cells; tumour necrosis factor-
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