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MBC in Press, published online ahead of print July 25, 2007
Mol. Biol. Cell 10.1091/mbc.E06-12-1096

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Submitted on December 11, 2006
Revised on June 11, 2007
Accepted on July 13, 2007

Tumor Cell Apoptosis Polarizes Macrophages—Role of Sphingosine-1-Phosphate

Andreas Weigert,* Nico Tzieply,* Andreas von Knethen,* Axel M. Johann,* Helmut Schmidt,{dagger} Gerd Geisslinger,{dagger} and Bernhard Brüne*

Institutes of *Biochemistry I/ZAFES and {dagger}Clinical Pharmacology/ZAFES, Johann Wolfgang Goethe-University, 60590 Frankfurt, Germany

Monitoring Editor: J. Silvio Gutkind

Macrophage polarization contributes to a number of human pathologies. This is exemplified for tumor-associated macrophages (TAM), which display a polarized M2 phenotype, closely associated with promotion of angiogenesis and suppression of innate immune responses. We present evidence that induction of apoptosis in tumor cells and subsequent recognition of apoptotic debris by macrophages participates in the macrophage phenotype shift. During coculture of human primary macrophages with human breast cancer carcinoma cells (MCF-7) the latter ones were killed, while macrophages acquired an alternatively activated phenotype. This was characterized by decreased tumor necrosis factor (TNF)-{alpha} and interleukin 12-p70 production, but increased formation of interleukins 8 and 10. Alternative macrophage activation required tumor cell death because a coculture with apoptosis-resistant colon carcinoma cells (RKO) or Bcl-2 overexpressing MCF-7 cells failed to induce phenotype alterations. Interestingly, phenotype alterations were achieved with conditioned media from apoptotic tumor cells, arguing for a soluble factor. Knockdown of sphingosine kinase (Sphk) 2, but not Sphk1, to attenuate S1P formation in MCF-7 cells, restored classical macrophage responses during coculture. Furthermore, macrophage polarization achieved by tumor cell apoptosis or substitution of authentic S1P suppressed nuclear factor (NF)-{kappa}B signaling. These findings suggest that tumor cell apoptosis-derived S1P contributes to macrophage polarization.

Address correspondence to: Bernhard Brüne (bruene{at}zbc.kgu.de)




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A. M. Johann, A. Weigert, W. Eberhardt, A.-M. Kuhn, V. Barra, A. von Knethen, J. M. Pfeilschifter, and B. Brune
Apoptotic Cell-Derived Sphingosine-1-Phosphate Promotes HuR-Dependent Cyclooxygenase-2 mRNA Stabilization and Protein Expression
J. Immunol., January 15, 2008; 180(2): 1239 - 1248.
[Abstract] [Full Text] [PDF]


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