Nuclear factor-kappaB-dependent reversal of aging-induced alterations in T cell cytokines.
Immunosenescence is characterized by decreases in protective immune responses and increases in inflammation and autoimmunity. The T helper (Th)17 subset of cluster-of-differentiation (CD)4 T cells, which is identified by its generation of interleukin (IL) -17, is implicated in autoimmune pathogenesis. To elucidate immunosenescent changes in Th17 cell cytokines, splenic CD4 T cells from 22- to 24-month-old (old) mice and 6- to 10-wk-old (young) mice were incubated on anti-CD3 plus anti-CD28 (anti-T cell antigen receptor) antibodies. After 96 h, T cells of old C57BL/6 and CBA mice generated up to 20-fold more IL-17 and up to 3-fold more IL-6 than those of young mice; T cells of young mice generated up to 5-fold more IL-21 than those of old mice; and no difference was found for IFN-gamma. At 24 h, cytokine mRNA levels paralleled 96 h cytokine concentrations. Naive CD4 T cells from old mice incubated on anti-T cell antigen receptor antibodies with transforming growth factor-beta, IL-1, IL-6, and IL-23 to induce de novo differentiation of Th17 cells had more IL-17 mRNA and produced more IL-17 than those of young mice. BAY11-7082 and the phytochemicals triptolide and butein suppressed nuclear concentrations of nuclear factor-kappaB and secreted levels of IL-17, IL-21, and IFN-gamma in parallel, with greater potency in Th17 cells from young than old mice. Pharmacological correction of altered generation of Th17 cell cytokines in immunosenescence represents a novel therapeutic approach to aging-induced inflammatory diseases.
Huang
Mei-Chuan
MC
Department of Medicine, University of California, San Francisco, California, USA.
Liao
Jia-Jun
JJ
Bonasera
Stephen
S
Longo
Dan L
DL
Goetzl
Edward J
EJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D008214:Lymphocytes / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016328:NF-kappa B / Q000502:physiology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000502:physiology*; D000098546:Interleukin-21
D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D016328:NF-kappa B; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; D000098546:Interleukin-21