Age-related reductions in the activation of mitogen-activated protein kinases p44mapk/ERK1 and p42mapk/ERK2 in human T cells stimulated via ligation of the T cell receptor complex.
Age-related changes in the functional properties of human T cells are well described, but less is known about possible changes in T cell signaling pathways. The signaling pathways mediated by mitogen-activated protein kinases (MAPK) are considered essential for normal cellular growth and function. Several stimuli trigger MAPK activation in human T cells and MEK (MAPK or ERK kinases) are immediate upstream inducers of MAPK activation. The current study investigated if aging might influence the activation and expression of MAPK and MEK in human T cells. Exposure of peripheral blood T cells from young subjects to PHA or cross-linked anti-CD3 monoclonal antibodies stimulated rapid increases in MAPK and MEK enzymatic activity. By contrast, significant reductions of MAPK and MEK activation were observed in stimulated T cells from 7 of 13 elderly subjects. Kinetic studies showed that the age-related impairments represented reduction in both the levels and duration of MAPK activation. In addition, Western immunoblot analysis did not reveal significant age-related differences in T cell expression of p42mapk/ERK2, p44mapk/ERK1, or MEK, suggesting impairments in upstream inducers of MEK/MAPK activation. Other experiments determined if agents that directly stimulate upstream Ras or Raf kinase components of the early MAPK cascade might reverse the age-related impairments of MAPK activation. Treatment of elderly T cells with fluoroaluminate (AlF(-)4), phorbol esters/Ca2+ ionophores, or okadaic acid stimulated increased MAPK activation compared to anti-CD3. However, these agents failed to restore MAPK activation in elderly T cells to the levels seen in young T cells. These results suggest that aberrancies in the MAPK activation cascade may underlie the age-related reductions of MAPK activation in human T cells stimulated via the TCR/CD3 complex.
Whisler
R L
RL
Department of Medical Biochemistry, William H. Davis Medical Research Center, Ohio State University, Columbus 43210-1228, USA.
Newhouse
Y G
YG
Bagenstose
S E
SE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology* / Q000378:metabolism; D000595:Amino Acid Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004988:Ethers, Cyclic / Q000494:pharmacology; D005260:Female; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D037102:Lectins / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D016853:Muromonab-CD3 / Q000494:pharmacology*; D019319:Okadaic Acid; D010766:Phosphorylation / Q000187:drug effects; D010835:Phytohemagglutinins / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000187:drug effects / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004988:Ethers, Cyclic; D007476:Ionophores; D007527:Isoenzymes; D037102:Lectins; D016853:Muromonab-CD3; D010835:Phytohemagglutinins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D019319:Okadaic Acid; D015759:Ionomycin; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate