Reactive oxygen species regulate quiescent T-cell apoptosis via the BH3-only proapoptotic protein BIM.
The survival of quiescent T cells in the peripheral immune system is dependent on signals transmitted from the extracellular environment. The requirement for survival factors is also manifested in vitro, providing a robust system to examine molecular mechanisms underlying T-cell death. We show that peripheral T cells cultured in the absence of survival factors accumulate reactive oxygen species (ROS), upregulate BIM (Bcl-2-interacting mediator of death) and inducible nitric oxide synthase (iNOS) expression, culminating in Fas-independent neglect-induced death (NID). We have examined ROS, iNOS and cytokine modulation of T-cell NID. Antioxidants inhibit BIM induction, caspase activation and apoptosis but do not promote cell cycle entry. iNOS-deficient T cells are protected from apoptosis, implicating iNOS in the regulation of NID via suppression of Bcl-x(L) expression and consequent inhibition of BIM activity. Finally, we show that the prosurvival cytokine IL-7 elevates Bcl-x(L) expression and transcriptionally regulates iNOS but not BIM expression in T cells.
Sade
H
H
National Centre for Biological Sciences, UAS-GKVK Campus, Bangalore, India.
Sarin
A
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051020:bcl-X Protein
D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C494812:Bcl2l1 protein, mouse; C000606776:Bcl2l11 protein, mouse; D002352:Carrier Proteins; D015851:Interleukin-7; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051020:bcl-X Protein; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020169:Caspases