Tyrosine phosphorylation-dependent activation of NFkappaB is compromised in T cells from the elderly.
NFkappaB induction and gene regulation are compromised in T lymphocytes during aging. This has been attributed to altered proteasomal function resulting in decreased ubiquitin-mediated degradation of IkappaBalpha. However, little is known about the impact of aging on the mechanisms that lead to the release of active NFkappaB employing pro-oxidant pathways. Oxidant-mediated activation of NFkappaB has been previously shown to involve proteasome independent mechanisms and hence may be an important alternate conduit to the induction of this central transcription factor in aging. Employing H(2)O(2) and pervanadate we not only demonstrate lowered tyrosine phosphorylation of IkappaBalpha, but also compromised induction of nuclear NFkappaB in T cells from the elderly. Lowered tyrosine phosphorylation of IkappaBalpha may be due to a decrease in activity of p56(lck) and ZAP-70, since treatment with piceatannol, an inhibitor of syk and src family kinases, mimics age associated decline in tyrosine phosphorylation of IkappaBalpha in T cells from young donors. Thus, alternate pathways of NFkappaB induction are also impaired in T cells from the elderly and may underlie immune-deficit accompanying aging.
Ponnappan
Subramaniam
S
Department of Geriatrics, University of Arkansas for Medical Sciences, Medical research, CAVHS, GC 143, 151LR/VA, 4300 West 7th, Little Rock, AR 72205, USA.
Uken-Trebilcock
Gina
G
Lindquist
Michael
M
Ponnappan
Usha
U
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000378:metabolism*; D014443:Tyrosine / Q000502:physiology*; D014638:Vanadates / Q000494:pharmacology
D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C076715:pervanadate; D000072000:NF-KappaB Inhibitor alpha; D014638:Vanadates; D014443:Tyrosine; D006861:Hydrogen Peroxide; D017027:Protein Tyrosine Phosphatases