Mechanisms of Apoptosis of T-Cells in Human Tuberculosis |
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| Authors: | Christina S. Hirsch John L. Johnson Alphonse Okwera Richard A. Kanost Mianda Wu Pierre Peters Mathew Muhumuza Harriet Mayanja-Kizza Roy D. Mugerwa Peter Mugyenyi Jerrold J. Ellner Zahra Toossi |
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| Affiliation: | (1) Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio;(2) Ugandan Ministry of Health, National Tuberculosis and Leprosy Programme, Kampala, Uganda;(3) Joint Clinical Research Centre, Kampala, Uganda;(4) Makerere University, Kampala, Uganda;(5) University of Medicine and Dentistry, Newark, New Jersey;(6) Veterans Affairs Medical Center, Cleveland, Ohio;(7) Department of Medicine, Division of Infectious Diseases, BRB 10W, 10900 Euclid Ave, Cleveland, Ohio, 44106-4984 |
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| Abstract: | The role of TGF-β TNF-α 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-β or TNF-α decreased spontaneous (P ≤ 0.05) and MTB-induced (P≤ 0.02) T-cell apoptosis by 50–90%, but effects were not additive. Interestingly, only levels of TGF-β 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 ≤ 0.02), and MTB stimulation reduced intracellular Bcl-2 content in CD4 T-cells from patients only (P ≤ 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-β TNF-α and FasL. |
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| Keywords: | Tuberculosis apoptosis TGF-β TNF-α Bcl-2 |
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