DIFFERENTIAL EXPRESSION OF FAS (CD95) AND FAS LIGAND ON NORMAL HUMAN PHAGOCYTES - IMPLICATIONS FOR THE REGULATION OF APOPTOSIS IN NEUTROPHILS

Human neutrophils, monocytes, and eosinophils are known to undergo apo ptotic cell death. The Fas/Fas ligand pathway has been implicated as a n important cellular pathway mediating apoptosis in diverse cell types . We conducted studies to examine the importance of the Fas/FasL syste m in normal human phagocytes. Although Fas expression was detected on neutrophils, monocytes, and eosinophils, constitutive expression of Fa sL was restricted to neutrophils. The three types of phagocytes demons trated differential sensitivity to Fas-induced apoptosis. Only neutrop hils were highly susceptible to rapid apoptosis in vitro after stimula tion with activating anti-Fas IgM (mAb Ch-11). Fas-mediated neutrophil apoptosis was suppressed by incubation with G-CSF, GM-CSF, IFN-gamma, TNF-alpha, or dexamethasone, as well as the selective tyrosine kinase inhibitors, herbimycin A and genistein. Spontaneous neutrophil death in vitro was partially suppressed by Fas-Ig fusion protein or antagoni stic anti-Fas IgG(1) (mAb ZB4). In coculture experiments, neutrophils released a soluble factor inducting death in Fas-susceptible Jurkat ce lls via a mechanism sensitive to the presence of Fas-Ig or anti-Fas Ig G(1). Immunoblot analysis using specific anti-human FasL IgG(1) (mAb N o. 33) identified a 37-kD protein in lysates of freshly isolated neutr ophils and a 30-kD protein in the culture supernatant of neutrophils m aintained in vitro. Our results suggest that mature neutrophils may be irrevocable committed to autocrine death by virtue of their constitut ive coexpression of cell-surface Fas and FasL via a mechanism that is sensitive to proinflammatory cytokines, glucocorticoids, and inhibitor s of tyrosine kinase activity. Furthermore, neutrophils can serve as a source of soluble FasL, which may function in a paracrine pathway to mediate cell death.