CXCL4-induced monocyte survival, cytokine expression, and oxygen radical formation is regulated by sphingosine kinase 1.
Human monocytes respond to a variety of stimuli with a complex spectrum of activities ranging from acute defense mechanisms to cell differentiation or cytokine release. However, the individual intracellular signaling pathways related to these functions are not well understood. CXC chemokine ligand 4 (CXCL4) represents a broad activator of monocytes, which induces acute as well as delayed activities in these cells including cell differentiation, survival, or the release of ROS, and cytokines. Here, we report for the first time that CXCL4-treated monocytes significantly upregulate sphingosine kinase 1 (SphK1) mRNA and that CXCL4 induces SphK1 enzyme activity as well as its translocation to the cell membrane. Furthermore, we could show that pharmacological inhibition of SphK results in reversal of CXCL4-induced monocyte survival, cytokine expression, and release of oxygen radicals, which was confirmed by the use of SphK1-specific siRNA. CXCL4-mediated rescue from apoptosis, which is accompanied by inhibition of caspases, is controlled by SphK1 and its downstream element Erk. Taken together, these data assign SphK1 as a central regulator of acute and delayed monocyte activation and suggest SphK1 as a potential therapeutic target to suppress pro-inflammatory responses induced by CXCL4.
Kasper
Brigitte
B
Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany. bkasper@fz-borstel.de
Winoto-Morbach
Supandi
S
Mittelstädt
Jessica
J
Brandt
Ernst
E
Schütze
Stefan
S
Petersen
Frank
F
D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D010978:Platelet Factor 4 / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000099157:Sphingosine Kinase
D061945:Caspase Inhibitors; D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D037342:Pertussis Toxin; D017853:Phosphotransferases (Alcohol Group Acceptor); D010978:Platelet Factor 4; D017382:Reactive Oxygen Species; D000099157:Sphingosine Kinase