Melatonin protects CD4+ T cells from activation-induced cell death by blocking NFAT-mediated CD95 ligand upregulation.
Over the past 20 y, the hormone melatonin was found to be produced in extrapineal sites, including cells of the immune system. Despite the increasing data regarding the biological effects of melatonin on the regulation of the immune system, the effect of this molecule on T cell survival remains largely unknown. Activation-induced cell death plays a critical role in the maintenance of the homeostasis of the immune system by eliminating self-reactive or chronically stimulated T cells. Because activated T cells not only synthesize melatonin but also respond to it, we investigated whether melatonin could modulate activation-induced cell death. We found that melatonin protects human and murine CD4(+) T cells from apoptosis by inhibiting CD95 ligand mRNA and protein upregulation in response to TCR/CD3 stimulation. This inhibition is a result of the interference with calmodulin/calcineurin activation of NFAT that prevents the translocation of NFAT to the nucleus. Accordingly, melatonin has no effect on T cells transfected with a constitutively active form of NFAT capable of migrating to the nucleus and transactivating target genes in the absence of calcineurin activity. Our results revealed a novel biochemical pathway that regulates the expression of CD95 ligand and potentially other downstream targets of NFAT activation.
Pedrosa
Alziana Moreno da Cunha
AM
Departamento de Análises Clínica e Toxicológica, Faculdade de Ciências Farmacêuticas, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo Brazil.
Weinlich
Ricardo
R
Mognol
Giuliana Patricia
GP
Robbs
Bruno Kaufmann
BK
Viola
João Paulo de Biaso
JP
Campa
Ana
A
Amarante-Mendes
Gustavo Pessini
GP
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D053222:Fas Ligand Protein / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008550:Melatonin / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D050778:NFATC Transcription Factors / Q000276:immunology* / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D053222:Fas Ligand Protein; D050778:NFATC Transcription Factors; D008550:Melatonin