LPS induces apoptosis in macrophages mostly through the autocrine production of TNF-alpha

The deleterious effects of lipopolysaccharide (LPS) during endotoxic shock are associated with the secretion of tumor necrosis factor (TNF) and the pr oduction of nitric oxide (NO), both predominantly released by tissue macrop hages. We analyzed the mechanism by which LPS induces apoptosis in bone mar row-derived macrophages (BMDM), LPS-induced apoptosis reached a plateau at about 6 hours of stimulation, whereas the production of NO by the inducible NO-synthase (iNOS) required between 12 and 24 hours. Furthermore, LPS-indu ced early apoptosis was only moderately reduced in the presence of an inhib itor of iNOS or when using macrophages from iNOS -/-mice, In contrast, earl y apoptosis was paralleled by the rapid secretion of TNF and was almost abs ent in macrophages from mice deficient for one (p55) or both (p55 and p75) TNF-receptors, During the late phase of apoptosis (12-24 hours) NO signific antly contributed to the death of macrophages even in the absence of TNF-re ceptor signaling. NO-mediated cell death, but not apoptosis induced by TNF, correlated with the induction of p53 and Bar genes. Thus, LPS-induced apop tosis results from 2 independent mechanisms: first and predominantly, throu gh the autocrine secretion of TNF-alpha (early apoptotic events), and secon d, through the production of NO (late phase of apoptosis). (C) 2000 by The American Society of Hematology.