期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 25, 页码 21067-21081出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.324269
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资金
- Italian Ministry of Education, University and Scientific Research
- Italian Ministry of Health
- University of Genova
- Fondazione CARIGE
- Compagnia di S. Paolo
- Regione Liguria
- Fondazione Italiana Sclerosi Multipla (FISM)
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [8761]
Intracellular NAD(+) levels ([NAD(+)](i)) are important in regulating human T lymphocyte survival, cytokine secretion, and the capacity to respond to antigenic stimuli. NAD(+)-derived Ca2+-mobilizing second messengers, produced by CD38, play a pivotal role in T cell activation. Here we demonstrate that [NAD(+)] i modifications in T lymphocytes affect intracellular Ca2+ homeostasis both in terms of mitogen-induced [Ca2+](i) increase and of endoplasmic reticulum Ca2+ store replenishment. Lowering [NAD(+)](i) by FK866-mediated nicotinamide phosphoribosyltransferase inhibition decreased the mitogen-induced [Ca2+](i) rise in Jurkat cells and in activated T lymphocytes. Accordingly, the Ca2+ content of thapsigargin-sensitive Ca2+ stores was greatly reduced in these cells in the presence of FK866. When NAD(+) levels were increased by supplementing peripheral blood lymphocytes with the NAD(+) precursors nicotinamide, nicotinic acid, or nicotinamide mononucleotide, the Ca2+ content of thapsigargin-sensitive Ca2+ stores as well as cell responsiveness to mitogens in terms of [Ca2+](i) elevation were up-regulated. The use of specific siRNA showed that the changes of Ca2+ homeostasis induced by NAD(+) precursors are mediated by CD38 and the consequent ADPR-mediated TRPM2 gating. Finally, the presence of NAD(+) precursors up-regulated important T cell functions, such as proliferation and IL-2 release in response to mitogens.
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