title: Mechanisms of apoptosis of T-cells in human tuberculosis.
abstract: The role of TGF-beta TNF-alpha FasL and Bcl-2 in apoptosis of CD4 T-cells during active TB was studied. Coculture of PBMC from TB patients with neutralizing antibodies to TGF-beta or TNF-alpha decreased spontaneous (P < or = 0.05) and MTB-induced (P < or = 0.02) T-cell apoptosis by 50-90%, but effects were not additive. Interestingly, only levels of TGF-beta in supernatants correlated with rates of spontaneous and MTB-induced apoptosis. FasL surface and mRNA expression were higher in unstimulated and MTB-stimulated PBMC from patients than controls, and neutralization of FasL abrogated apoptosis of T-cells from patients only. Intracellular Bcl-2 protein was lower among unstimulated CD4 T-cells from patients than those from controls (P < or = 0.02), and MTB stimulation reduced intracellular Bcl-2 content in CD4 T-cells from patients only (P < or = 0.001). These findings may indicate that, during TB, predisposition of CD4 T-cells to apoptosis may involve both low expression of Bcl-2, and excessive expression of TGF-beta TNF-alpha and FasL.
authors.affiliation: Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio 44106-4984, USA. cxh40@po.cwru.edu
authors.forename: Christina S
authors.initials: CS
authors.lastname: Hirsch
authors.forename: John L
authors.initials: JL
authors.lastname: Johnson
authors.forename: Alphonse
authors.initials: A
authors.lastname: Okwera
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kanost
authors.forename: Mianda
authors.initials: M
authors.lastname: Wu
authors.forename: Pierre
authors.initials: P
authors.lastname: Peters
authors.forename: Mathew
authors.initials: M
authors.lastname: Muhumuza
authors.forename: Harriet
authors.initials: H
authors.lastname: Mayanja-Kizza
authors.forename: Roy D
authors.initials: RD
authors.lastname: Mugerwa
authors.forename: Peter
authors.initials: P
authors.lastname: Mugyenyi
authors.forename: Jerrold J
authors.initials: JJ
authors.lastname: Ellner
authors.forename: Zahra
authors.initials: Z
authors.lastname: Toossi
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D015536:Down-Regulation / Q000276:immunology; D053222:Fas Ligand Protein / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D047889:Receptors, Tumor Necrosis Factor, Type II; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor