Cyclodextrin modulation of T lymphocyte signal transduction with aging.
There is an alteration of the immune response in aging that leads to the increased incidence of infections, cancers and autoimmune disorders. The aim of the present study was to investigate whether there exists changes in signal transduction under the IL-2 receptor stimulation and the role of plasma membrane cholesterol in the activation of T cells with aging. We report age-related changes in the JAK-STAT signalling pathway that results in decreased tyrosine phosphorylation of STAT5. We present evidence for the importance of cholesterol content in regulating signalling pathways in T cells and in modulating their proliferation by using the plasma membrane cholesterol-depleting agent methyl-beta-cyclodexrin (MBCD). MBCD treatment (0.5 mM) induced a significant decrease in the cholesterol content of T cells of elderly subjects whereas it was increased in T cells of young subjects. MBCD induced changes in the phosphorylation of p56(lck), especially in T cells of elderly subjects. The proliferation of MBCD-treated T cells decreased in lymphocytes of young subjects but did not change in T cells of elderly subjects. These results suggest a role for plasma membrane cholesterol in the regulation of the TcR signalling pathways with differential effects related to aging. However, the data suggest that modulation of the plasma membrane cholesterol content alone may not be enough to restore signal transduction changes with aging.
Fülöp
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Centre de Recherche en Gérontologie et Gériatrie, Institut Universitaire de Geriatrie de Sherbrooke, 1036 rue Belvedère sud, Sherbrooke, Québec, Canada, J1H 4C4. tfulop@courrier.usherb.ca
Douziech
N
N
Goulet
A C
AC
Desgeorges
S
S
Linteau
A
A
Lacombe
G
G
Dupuis
G
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003505:Cyclodextrins / Q000378:metabolism* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D053616:Janus Kinase 3; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008297:Male; D008894:Milk Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D014443:Tyrosine; D002784:Cholesterol; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases