Published online before print May 20, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1004569

Received for publication October 7, 2004.
Revised February 24, 2005.
Accepted for publication April 21, 2005.

Article

PGE₂ confers survivin-dependent apoptosis resistance in human monocyte-derived dendritic cells

UCLA Lung Cancer Research Program of the Jonsson Comprehensive Cancer Center and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Geffen School of Medicine at University of California Los Angeles; and Molecular Gene Medicine Laboratory, Veteran’s Affairs Greater Los Angeles Healthcare System, California

^@ To whom correspondence should be addressed. E-mail: sdubinett{at}mednet.ucla.edu.

Abstract

Control of apoptosis is fundamental for dendritic cell (DC) homeostasis. Numerous factors maintain DC viability throughout their lifespan, including inhibitor of apoptosis proteins. Among them, survivin is overexpressed in many human malignancies, but its physiological function in normal cells has not been fully delineated. Prostaglandin E₂ (PGE₂), also overproduced in several malignancies, has shown to induce proapoptotic and antiapoptotic effects in different cell types, including immune cells. In DC, PGE₂ predominantly affects maturation and modulates immune functions. Here, we show that exposure of monocyte-derived DC to PGE₂ (10^-5 M) for 72 h significantly increased DC survivin mRNA and protein expression. In contrast, DC, matured with lipopolysaccharide or tumor necrosis factor , did not reveal survivin induction in response to PGE₂. Following exposure to apoptotic stimuli, DC treated with PGE₂ exhibited an overall increased viability compared with control DC, and this effect was correlated inversely with caspase-3 activation. Moreover, PGE₂-treated, survivin-deficient DC demonstrated reduced viability in response to apoptotic stimuli. Further analysis indicated that PGE₂ induced DC survivin expression in an E prostanoid (EP)₂/EP₄ receptor and phosphatidylinositol-3 kinase-dependent manner. These findings suggest that PGE₂-dependent regulation of survivin is important in modulating apoptosis resistance in human DC.

Key Words: lipid mediators • immune cells • antiapoptotic proteins

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