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Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Sep;1864(9):1235-1246. doi: 10.1016/j.bbalip.2019.05.008. Epub 2019 May 23.

Sphingosine kinase 2 is a negative regulator of inflammatory macrophage activation.

Author information

1
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
2
Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.
3
Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany; Branch for Translational Medicine and Pharmacology TMP of the Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 60590 Frankfurt, Germany.
4
Institut für Allgemeine Pharmakologie und Toxikologie, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
5
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; Branch for Translational Medicine and Pharmacology TMP of the Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 60590 Frankfurt, Germany. Electronic address: b.bruene@biochem.uni-frankfurt.de.

Abstract

Sphingosine kinases (SPHK) generate the sphingolipid sphingosine-1-phosphate, which, among other functions, is a potent regulator of inflammation. While SPHK1 produces S1P to promote inflammatory signaling, the role of SPHK2 is unclear due to divergent findings in studies utilizing gene depletion versus inhibition of catalytic activity. We sought to clarify how SPHK2 affects inflammatory signaling in human macrophages, which are main regulators of inflammation. SPHK2 expression and activity were rapidly decreased within 6 h upon stimulating primary human macrophages with lipopolysaccharide (LPS), but was upregulated after 24 h. At 24 h following LPS stimulation, targeting SPHK2 with the inhibitor ABC294640, a specific siRNA or by using Sphk2-/- mouse peritoneal macrophages increased inflammatory cytokine production. Downregulation of SPHK2 in primary human macrophages within 6 h of LPS treatment was blocked by inhibiting autophagy. SPHK2 overexpression or inhibiting autophagy 6 h after human macrophage activation with LPS suppressed inflammatory cytokine release. Mechanistically, SPHK2 suppressed LPS-triggered NF-κB activation independent of its catalytic activity and prevented increased mitochondrial ROS formation downstream of LPS. In conclusion, SPHK2 is an anti-inflammatory protein in human macrophages that is inversely coupled to inflammatory cytokine production. This needs consideration when targeting SPHK2 with specific inhibitors.

KEYWORDS:

Autophagy; Inflammation; Macrophage; Sphingolipids

PMID:
31128248
DOI:
10.1016/j.bbalip.2019.05.008
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