Mechanisms of apoptosis of T-cells in human tuberculosis.
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.
Hirsch
Christina S
CS
Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio 44106-4984, USA. cxh40@po.cwru.edu
Johnson
John L
JL
Okwera
Alphonse
A
Kanost
Richard A
RA
Wu
Mianda
M
Peters
Pierre
P
Muhumuza
Mathew
M
Mayanja-Kizza
Harriet
H
Mugerwa
Roy D
RD
Mugyenyi
Peter
P
Ellner
Jerrold J
JJ
Toossi
Zahra
Z
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
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