Nitric oxide-mediated inhibition of caspase-dependent T lymphocyte proliferation.
Nitric oxide (NO), a pleiotropic signaling molecule produced at sites of inflammation, is a powerful inhibitor of lymphocyte proliferation. Caspases, central effector proteases in apoptosis, have recently been implicated as critical mediators of T cell activation. We and others have shown that NO can inhibit caspases by S-nitrosylation, which is reversible by the reducing agent dithiothreitol (DTT). The purpose of the present study was to determine whether NO inhibits lymphocyte proliferation by modulating caspase activity. Caspase inhibition with z-VAD-fmk blocked T cell proliferation. NO-dependent inhibition of T cell proliferation was associated with an inhibition of caspase activity and activation, and this effect was reversible by DTT. Previous studies demonstrated inhibition of apoptosis through S-nitrosylation of caspases; the present studies extend this effect to inhibition of caspase-dependent T cell proliferation.
Mahidhara
Raja S
RS
Department of Surgery, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA. mahidharar@msx.upmc.edu
Hoffman
Rosemary A
RA
Huang
Sulan
S
Wolf-Johnston
Amanda
A
Vodovotz
Yoram
Y
Simmons
Richard L
RL
Billiar
Timothy R
TR
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004229:Dithiothreitol / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000378:metabolism*
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D016166:Free Radical Scavengers; D007376:Interleukin-2; D020030:Nitric Oxide Donors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D020169:Caspases; D004229:Dithiothreitol