DISRUPTION OF FAS RECEPTOR SIGNALING BY NITRIC-OXIDE IN EOSINOPHILS

It has been suggested that Fas Ligand-Fas receptor interactions are in volved 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 oxi de (NO) specifically prevents Fas receptor-mediated apoptosis in fresh ly isolated human eosinophils. In contrast, rapid acceleration of eosi nophil apoptosis by activation of the Fas receptor occurs in the prese nce of eosinophil hematopoietins. Analysis of the intracellular mechan isms revealed that NO disrupts Fas receptor-mediated signaling events at the level of, or proximal to, Jun kinase (JNK), but distal to sphin gomyelinase (SMase) activation and ceramide generation. In addition, a ctivation of SMase occurs downstream of an interleukin 1 converting en zyme-like (ICE-like) protease(s) that is not blocked by NO. However, N O prevents activation of a protease that targets lamin B-1. These find ings suggest a role for an additional NO-sensitive apoptotic signaling pathway that amplifies the proteolytic cascade initialized by activat ion of the Fas receptor. Therefore, NO concentrations within allergic inflammatory sites may be important in determining whether an eosinoph il survives or undergoes apoptosis upon Fas Ligand stimulation.