Disruption of fas receptor signaling by nitric oxide in eosinophils.
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.
Hebestreit
H
H
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, CH-7270 Davos, Switzerland.
Dibbert
B
B
Balatti
I
I
Braun
D
D
Schapowal
A
A
Blaser
K
K
Simon
H U
HU
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism*; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006651:Histocytochemistry; D006801:Humans; D015151:Immunoblotting; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009298:Nasal Polyps / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000032:analysis; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D009569:Nitric Oxide; D012313:RNA; D019001:Nitric Oxide Synthase