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J. Exp. Med.,
Volume 187, Number 3, February 2, 1998 415-425
By
From the * Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, CH-7270
Davos, Switzerland; and the It has been suggested that Fas ligand-Fas receptor interactions are involved in the regulation of
eosinophil apoptosis and that dysfunctions in this system could contribute to the accumulation of these cells in allergic and asthmatic diseases. Here, we demonstrate that nitric oxide (NO)
specifically prevents Fas receptor-mediated apoptosis in freshly isolated human eosinophils. In
contrast, rapid acceleration of eosinophil apoptosis by activation of the Fas receptor occurs in
the presence of eosinophil hematopoietins. Analysis of the intracellular mechanisms revealed
that NO disrupts Fas receptor-mediated signaling events at the level of, or proximal to, Jun kinase (JNK), but distal to sphingomyelinase (SMase) activation and ceramide generation. In addition, activation of SMase occurs downstream of an interleukin 1 converting enzyme-like
(ICE-like) protease(s) that is not blocked by NO. However, NO prevents activation of a protease that targets lamin B1. These findings suggest a role for an additional NO-sensitive apoptotic signaling pathway that amplifies the proteolytic cascade initialized by activation of the
Fas receptor. Therefore, NO concentrations within allergic inflammatory sites may be important in determining whether an eosinophil survives or undergoes apoptosis upon Fas ligand
stimulation.
Clinic for Dermatology and Allergy, Tobelmühlestrasse 2, CH-7270
Davos, Switzerland
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