IKK antagonizes activation-induced cell death of CD4+ T cells in aged mice via inhibition of JNK activation.
T cell dysfunction is the primary immunologic abnormality associated with aging. Many age-related defects stem from a decline in CD4(+) T cell function. Resistance of aged CD4(+) T cells to apoptosis is associated with autoimmune and infectious diseases. Previous studies suggest that IκB kinase (IKK) may be a key player in cell survival via its inhibition of c-Jun N-terminal protein kinase (JNK) activation. However, the role of IKK-mediated JNK inactivation in the age-related apoptosis of T cells is unclear. Here, we report that splenic CD4(+) T cells in aged mice are resistant to activation-induced cell death (AICD) induced by anti-CD3 plus IL-2 stimulation. Furthermore, aged CD4(+) T cells display increased IKKβ activity that is associated with attenuated JNK activation. The IKKβ-mediated JNK inactivation in aged CD4(+) T cells reduces the degradation of c-FLIP(L) and the interaction of Bad with Bcl-X(L), but it increases the affinity of Bad for 14-3-3. Pretreatment of aged CD4(+) T cells with a specific IKK inhibitor, PS1145, increases the JNK activity blocked by IKKβ and consequently sensitizes the aged CD4(+) T cells to AICD. Our study thus demonstrates that IKK antagonizes the AICD of CD4(+) T cells in aged mice via inhibition of JNK activation.
Deng
Hongbin
H
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, #1 Tian Tan Xi Li, Beijing 100050, China. denghongbin024@hotmail.com
Mao
Genxiang
G
Zhang
Jingpu
J
Wang
Zhen
Z
Li
Diandong
D
D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D053938:DNA Fragmentation; D004789:Enzyme Activation / Q000502:physiology; D051550:I-kappa B Kinase / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology*
D051550:I-kappa B Kinase; D048670:MAP Kinase Kinase 4