Affiliation:
1. Department of Medicine, University of California, Irvine, CA 92697
Abstract
Abstract
Aging is characterized by increased T cell lymphopenia, T cell dysfunction, and increased serum TNF levels. In this study, we have examined the role of TNF-induced apoptosis in T cell deficiency in lymphocytes from aged humans. The constitutive expression of TNF receptors (TNFRI and TNFRII) and the adapter molecules, including TNFR-associated death domain protein (TRADD), TNFR-associated factor 2 (TRAF-2), and receptor interacting protein (RIP), were analyzed both at the protein level by flow cytometry or Western blotting, and at the mRNA level using quantitative PCR or Northern blotting in lymphocytes from aged and young subjects. The susceptibility of T cells to undergo TNF-induced apoptosis was analyzed using terminal deoxynucleotidyltransferase-mediated UTP-end-labeling (TUNEL) and DNA ladder assays. Caspase (caspase-8 and caspase-3) activation was compared between aged and young subjects using Western blotting and colorimetric assays. In lymphocytes from aged humans, there was an increased susceptibility of CD4+ and CD8+ T cells to undergo TNF-α-induced apoptosis, as observed by TUNEL assay and DNA fragmentation ladder assay. Increased TNF-α-induced apoptosis was also observed in both CD45RA+ and CD45RO+ T cells from aging subjects. An increased constitutive expression of TNFRI and TRADD and decreased expression of TNFRII and TRAF-2 were observed in lymphocytes from aged as compared with young controls. In addition, there was an early and increased activation of caspases (caspase-8 and caspase-3) involved in TNFR/TNF signaling pathway, as evident by early cleavage of caspase-8, poly(ADP-ribose) polymerase (PARP), and caspase-3 substrate DEVD-p-nitroamilide NA. These data suggest that an increased TNF-α-induced apoptosis may play a role in T cell deficiency associated with human aging.
Publisher
The American Association of Immunologists
Subject
Immunology,Immunology and Allergy
Reference44 articles.
1. Goeddel, D. V., B. B. Aggarwal, P. W. Gray, D. W. Leung, G. E. Nedwin, M. A. Palladino, J. S. Patton, D. Pennica, H. M. Shepard, B. J. Sugarman, G. H. W. Wong. 1986. Tumor necrosis factors: gene structure and biological activities. Cold Spring Harbor Symp. Quant. Biol. 51: 597
2. Fiers, W.. 1991. Tumor necrosis factor: characterization at the molecular, cellular and in vivo level. FEBS Lett. 285: 199
3. Beutler, B., A. Cerami. 1988. Tumor necrosis, cachexia, shock, and inflammation: a common mediator. Annu. Rev. Biochem. 57: 505
4. Ramshaw, I. A., A. J. Ramsay, G. Karupiah, M. S. Rolph, S. Mahalingam, J. C. Ruby. 1997. Cytokines and immunity to viral infections. Immunol. Rev. 159: 119
5. Herbein, G.. 1997. Cytokines, viruses and macrophages: an interactive network: an immune dysregulation involving the members of the tumor necrosis factor (TNF) receptor superfamily could be critical in AIDS pathogenesis. Pathol. Biol. 45: 115
Cited by
20 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献