Cell Growth & Differentiation, Vol 9, Issue 5 415-422, Copyright © 1998 by American Association of Cancer Research

ARTICLES

Nitric oxide inhibits APO-1/Fas-mediated cell death

S Dimmeler, J Haendeler, A Sause and AM Zeiher
Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Germany.

Activation of the cysteine protease caspases, which are homologous to the product of Caenorhabditis elegans cell-death gene ced 3, is required to mediate APO-1/Fas-induced apoptosis. We report here that nitric oxide (NO) released by exogenous NO donors, as well as NO endogenously derived by transfection with the inducible NO synthase, substantially suppresses APO-1/Fas-triggered cell death of Jurkat cells. The inhibitory NO effect was independent of cGMP, because 8-bromo-cGMP did not influence APO-1/Fas-mediated apoptosis. In contrast, NO interferes with the APO-1/Fas-induced stimulation of caspases. NO inhibits the proteolytic cleavage of caspase-3 (CPP32) into its active subunits, thereby suppressing caspase-3 activity. In addition, NO potently inhibits apoptosis induction by overexpresssion of the death domain protein FADD or the immediate downstream target caspase-8. These results suggest that NO modulates the proteolytic cascade upstream of caspase-3. Indeed, NO specifically S-nitrosylates caspase-8 and caspase-1 and thereby may prevent activation of the proteolytic cascade. The NO-mediated increase in the resistance toward induction of apoptosis may play a major role in mediating immune responses, as well as in the pathogenesis of autoimmune diseases.

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