© The Rockefeller University Press, 0022-1007/1998/2/415/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 3, February 2, 1998 415-425
Disruption of Fas Receptor Signaling by Nitric Oxide in Eosinophils
Holger Hebestreit*,
Birgit Dibbert*,
Ivo Balatti*,
Doris Braun
,
Andreas Schapowal
,
Kurt Blaser*, and
Hans-Uwe Simon*
From the * Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, CH-7270 Davos, Switzerland; and the
Clinic for Dermatology and Allergy, Tobelmühlestrasse 2, CH-7270 Davos, Switzerland
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.
Address correspondence to Dr. Hans-Uwe Simon, Swiss Institute of Allergy and Asthma Research, University of Zurich, Obere Strasse 22, CH-7270 Davos, Switzerland. Phone: +41-81-4137083; Fax: +41-81-4131607; E-mail: hus{at}SIAF.unizh.ch
1 Abbreviations used in this paper: DAG, 1,2-dioctanoyl-sn-glycerol; db, dibutyryl; DISC, death-inducing signaling complex; ECL, enhanced chemiluminescence; IBMX, 3-isobutyl-1-methylxanthine; ICE, IL-1 converting enzyme; iNOS, inducible isoform of NOS; JNK, Jun kinase; LY 83583, 6-anilinoquinoline-5,8-quinone; MAP, mitogen-activated protein; mRNA, messenger RNA; NMMA, NG-monomethyl-L-arginine; NO, nitric oxide; NOS, NO synthase; PS, phosphatidylserine; sGC, soluble guanylyl cyclase; SM, sphingomyelin; SMase, sphingomyelinase; SNAP, S-nitroso-N-acetylpenicillamine.

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