OxyFile #357

Fas mediates apoptosis in human monocytes by a reactive oxygen
intermediate dependent pathway.

Um HD; Orenstein JM; Wahl SM

Laboratory of Immunology, National Institute of Dental Research,
Bethesda, MD 20892, USA.

J Immunol, 156: 9, 1996 May 1, 3469-77

Abstract

Monocyte apoptosis has emerged as a central regulatory event in 
hemopoiesis and inflammation. Inflammatory cytokines can either 
promote or prevent monocyte apoptosis. To study the possible role 
of Fas Ag, a member of the TNF/nerve growth factor receptor 
family, in monocyte apoptosis, human peripheral blood monocytes 
activated by IL-1 beta or TNF-alpha were exposed to anti-Fas mAb. 
Engagement of the Fas Ag resulted in apoptosis of monocytes, as 
monitored by propidium iodide uptake, decrease in cell size, DNA 
fragmentation, and characteristic ultrastructural changes. The 
apoptotic action of Fas was abolished completely by antioxidants 
such as N-acetylcysteine and glutathione, suggesting a role for 
reactive oxygen intermediates (ROI) in the death process. 
Consistent with this observation, Fas stimulation enhanced the 
fluorescence associated with oxidation of 2',7'-
dichlorofluorescein, indicating increased levels of intracellular 
ROI. Moreover, the exogenous addition of hydrogen peroxide or 
menadione, an intracellular generator of superoxide anion, was 
sufficient for the induction of monocyte apoptosis. These data 
indicate that ROI are key mediators of Fas-induced apoptosis. In 
contrast to IL-1 beta and TNF-alpha, LPS-treated monocytes were 
resistant to the apoptotic action of Fas. Under these conditions, 
LPS did not down-regulate Fas, but inhibited the Fas-dependent 
elevation of ROI. Therefore, monocytes appear to have a protective 
mechanism that can interfere directly with the Fas-induced pathway 
of cell suicide, thereby controlling their destiny.