Age-sensitive and -insensitive pathways leading to JNK activation in mouse CD4(+) T-cells.
The c-Jun N-terminal kinase (JNK) can be activated in T-cells either by the combination of TCR and CD28 costimulation or by a variety of stress-related stimuli including UV light, H(2)O(2), and hyperosmolar sorbitol solutions. In T-lymphocytes, TCR/CD28 stimulation of JNK leads to induction of new gene expression via c-Jun, ATF-2, and Elk-1. Phosphorylation of c-Jun in CD4(+) T-cells stimulated by CD3/CD4/CD28 cross-linking declines with age, due to diminished activation of JNK. Here we show that the age-related decline in TCR/CD28 activation of JNK reflects two effects of age: the accumulation of memory cells (in which JNK stimulation is poor regardless of donor age) and age-dependent declines in JNK activation within the naive subset. Cyclosporin A inhibits induction of JNK function by TCR/CD28, PMA/ionomycin, ceramide, or H(2)O(2), but not induction by UV light or hyperosmolar sorbitol. Although aging impairs JNK induction by UV light, it has no effect on JNK activation by ceramide, H(2)O(2), or sorbitol. The data as a whole indicate that there are at least four pathways that activate JNK in CD4(+) T-cells, of which two are age-sensitive and two others unaffected by aging. Two of the pathways (UV and hyperosmolar sorbitol) are insensitive to cyclosporin inhibition. Finally, we show that the alterations in JNK function are not due to changes in the expression of MKK4, an upstream activator of JNK, and that another JNK kinase, MKK7, is not expressed in splenic T-cells.
Kirk
C J
CJ
Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Miller
R A
RA
D000375:Aging / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007156:Immunologic Memory; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D013012:Sorbitol / Q000494:pharmacology; D014466:Ultraviolet Rays
D002518:Ceramides; D005576:Colforsin; D013012:Sorbitol; D016572:Cyclosporine; D006861:Hydrogen Peroxide; D011505:Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; C482559:MAP2K4 protein, human; C482569:MAP2K7 protein, human; C482562:Map2k4 protein, mouse; C482570:Map2k7 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D004121:Dimethyl Sulfoxide