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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1635-1642. Prepublished online as a Blood First Edition Paper on May 11, 2006; DOI 10.1182/blood-2006-04-014852. This Article Full Text (PDF) All Versions of this Article: blood-2006-04-014852v1 108/5/1635    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Weigert, A. Articles by Brune, B. Search for Related Content PubMed PubMed Citation Articles by Weigert, A. Articles by Brune, B. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 4, 2006 Accepted April 25, 2006 Apoptotic cells promote macrophage survival by releasing the anti-apoptotic mediator sphingosine-1-phosphate Andreas Weigert, Axel M Johann, Andreas von Knethen, Helmut Schmidt, Gerd Geisslinger, and Bernhard Brune* University of Frankfurt Medical School, Frankfurt, Germany University of Frankfurt Medical School, Frankfurt Germany * Corresponding author; email: bruene{at}zbc.kgu.de. Programmed cell death is vital for a number of patho- physiological settings. Apoptotic cells are rapidly engulfed by phagocytes i.e. macrophages which in turn acquire an anti-inflammatory phenotype known as ‘ alternative activation’ or the M2-type. Here we show that interaction of apoptotic cells with macrophages attenuates cell death pathways in the latter ones. Protection of human macrophages required phosphoinositide 3-kinase (PI3K), extracellular signal- regulated kinase 1/2 (ERK1/2) and Ca2+ signaling, and correlated with Bcl-XL and Bcl-2 up-regulation as well as Ser136-Bad phosphorylation. Unexpectedly neither phagocytosis nor binding of apoptotic debris to the phagocyte was necessary to induce protection. Surprisingly, apoptotic cells released sphingosine-1- phosphate (S1P), mainly derived from sphingosine kinase 2, as a survival messenger. This points to an active role of apoptotic cells in preventing cell destruction in their neighborhood with implications for innate immunity and inflammation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Thorp and I. Tabas Mechanisms and consequences of efferocytosis in advanced atherosclerosis J. Leukoc. Biol., November 1, 2009; 86(5): 1089 - 1095. [Abstract] [Full Text] [PDF] B. Herr, J. Zhou, C. Werno, H. Menrad, D. Namgaladze, A. Weigert, N. Dehne, and B. Brune The supernatant of apoptotic cells causes transcriptional activation of hypoxia-inducible factor-1{alpha} in macrophages via sphingosine-1-phosphate and transforming growth factor-{beta} Blood, September 3, 2009; 114(10): 2140 - 2148. [Abstract] [Full Text] [PDF] C.-C. Yeh, H. Li, D. Malhotra, M.-C. Huang, B.-Q. Zhu, E. J. Goetzl, D. A. Vessey, J. S. Karliner, and M. J. Mann Sphingolipid signaling and treatment during remodeling of the uninfarcted ventricular wall after myocardial infarction Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H1193 - H1199. [Abstract] [Full Text] [PDF] S. E. Schnitzer, A. Weigert, J. Zhou, and B. Brune Hypoxia Enhances Sphingosine Kinase 2 Activity and Provokes Sphingosine-1-Phosphate-Mediated Chemoresistance in A549 Lung Cancer Cells Mol. Cancer Res., March 1, 2009; 7(3): 393 - 401. [Abstract] [Full Text] [PDF] N. Weis, A. Weigert, A. von Knethen, and B. 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