Ubiquitin-proteasome pathway is compromised in CD45RO+ and CD45RA+ T lymphocyte subsets during aging.
Recent reports from our laboratory have demonstrated that CD45RO+ and CD45RA+ T lymphocytes from the elderly are compromised in their response to activation-induced IL-2 receptor expression, IkappaB-alpha degradation, as well as nuclear translocation of NFkB. To understand the basis of this activation-induced dysfunction in the elderly, we have examined the role of the ubiquitin-proteasome pathway. Our results demonstrate that both CD45RO+ and CD45RA+ T lymphocytes from the elderly show significant reduction in the constitutive 26S proteasome-associated chymotryptic activity, when compared to those in the young. Additionally, anti-CD3-CD28 treatment induced enhancement of proteasome-associated enzymatic activity in cells from the young, but not in cells from the elderly. Lowered proteasome-associated activity and its effect on reduced immune responses in the elderly could be mimicked by experiments which involved pretreatment of T cells from young donors with a proteasome specific inhibitor, lactacystin. These data demonstrate that IL-2 receptor induction is clearly compromised in T cells from the young when proteasomes are inhibited by pretreatment with lactacystin. An examination of ubiquitin specific hydrolase activity, demonstrated a decrease in activated CD45RA+ and CD45RO+ T cell subsets from the elderly when compared to young. These results suggest that lowered proteasome-associated enzymatic activity in combination with compromised de-ubiquitinating activity may be responsible for lowered activation-induced NFkB and NFkB-mediated gene expression in elderly subjects.
Ponnappan
Usha
U
Department of Microbiology, University of Arkansas for Medical Sciences, CAVHS, GC 143, 151/LRVA, John L. McClellan Memorial VA Hospital, 4300 West 7th Street, Little Rock, AR 72205, USA. ponnappanusha@uams.edu
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D015415:Biomarkers; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D002918:Chymotrypsin / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D017493:Leukocyte Common Antigens; D008213:Lymphocyte Activation; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
D015415:Biomarkers; D018106:CD28 Antigens; D017252:CD3 Complex; D015853:Cysteine Proteinase Inhibitors; D009097:Multienzyme Complexes; D015375:Receptors, Interleukin-2; D025801:Ubiquitin; C067713:lactacystin; D017493:Leukocyte Common Antigens; D010447:Peptide Hydrolases; D002918:Chymotrypsin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D000111:Acetylcysteine