Role of NF-kappaB signaling pathway in increased tumor necrosis factor-alpha-induced apoptosis of lymphocytes in aged humans.
In human aging, lymphocytes display increased sensitivity to tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis. TNF-alpha induces both survival and apoptotic signals. The survival signal is mediated by the activation of NF-kappaB. Although a role of certain proapoptotic molecules in aging has been reported, a role of altered NF-kappaB signaling pathway has not been explored in detail. In this study, we have compared TNF-alpha-induced activation of NF-kappaB, phosphorylation of IkappaBalpha, and the expression of IKKbeta between lymphocytes from young and aged humans. Furthermore, we have explored a role of IKKbeta in increased susceptibility of lymphocytes from aged humans to TNF-alpha-induced apoptosis. Lymphocytes from aged humans displayed decreased activation of NF-kappaB, reduced phosphorylation of IkappaBalpha, and decreased expression of IKKbeta. In addition, overexpression of IKKbeta in lymphocytes from aged humans normalized TNF-alpha-induced apoptosis to the level of young subjects. These data suggest a deficiency of NF-kappaB signaling pathway and a role of IKKbeta, at least in part, for increased sensitivity of lymphocytes from aged humans to TNF-alpha-induced apoptosis.
Gupta
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S
Cellular and Molecular Immunology and Molecular Biology Laboratories, Division of Basic and Clinical Immunology, University of California, Irvine, CA 92697, USA. sgupta@uci.edu
Bi
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Kim
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Chiplunkar
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Yel
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Gollapudi
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D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
D020672:I-kappa B Proteins; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human