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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3823-3831
LPS induces apoptosis in macrophages mostly through the
autocrine production of TNF-
Jordi Xaus,
Mònica Comalada,
Annabel F. Valledor,
Jorge Lloberas,
Francisco López-Soriano,
Josep M. Argilés,
Christian Bogdan, and
Antonio Celada
From the Departament de Fisiologia (Biologia del Macròfag) and
Fundació August Pi i Sunyer, Campus de Bellvitge; Departament de
Bioquímica i Biologia Molecular, Facultat de Biologia
Universitat de Barcelona, Barcelona, Spain; and the Institut für
Klinische Mikrobiologie Immunologie und Hygiene, Universität
Erlangen, Erlangen, Germany.
The deleterious effects of lipopolysaccharide (LPS) during endotoxic
shock are associated with the secretion of tumor necrosis factor (TNF)
and the production of nitric oxide (NO), both predominantly released by
tissue macrophages. We analyzed the mechanism by which LPS induces
apoptosis in bone marrow-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-induced early apoptosis was
only moderately reduced in the presence of an inhibitor of iNOS or when
using macrophages from iNOS -/-mice. In contrast, early apoptosis was
paralleled by the rapid secretion of TNF and was almost absent 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
significantly contributed to the death of macrophages even in the
absence of TNF-receptor signaling. NO-mediated cell death, but not
apoptosis induced by TNF, correlated with the induction of p53 and Bax
genes. Thus, LPS-induced apoptosis results from 2 independent
mechanisms: first and predominantly, through the autocrine secretion of
TNF- (early apoptotic events), and second, through the production of
NO (late phase of apoptosis).
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