CXCL4‐induced monocyte survival, cytokine expression, and oxygen radical formation is regulated by sphingosine kinase 1

Abstract

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.Key words: Chemokines . Monocytes . Signal transduction . Sphingosine kinase IntroductionMonocytes are members of the mononuclear phagocyte system and represent one of the most flexible cell types within the immune system. These cells are critically important in the regulation of innate and adaptive immune responses by generation of inflammatory mediators, antigen presentation, phagocytosis, and killing of microorganisms. Monocytes are highly mobile cells and can rapidly accumulate at sites of inflammation. However, a successful defense requires not only the presence of monocytes at inflammatory sites but also fast and effective mechanisms for their activation. In previous reports we described monocyte activation by CXC chemokine ligand 4 (CXCL4; platelet factor 4) [1][2][3]. CXCL4 belongs to the family of CXC-chemokines and is rapidly released in high concentrations upon platelet activation [4,5]. Although no data exist in the literature concerning CXCL4 concentrations at a site of acute platelet activation in vivo, normal serum concentrations of CXCL4 (1-2.5 mM) [6] are sufficient to induce a full monocyte response [1]. Moreover, in regions of acute platelet activation where such platelet-monocyte interaction may take place, concentrations of CXCL4 are likely to be much higher.Although CXCL4 does not induce typical chemokine responses such as chemotaxis or calcium mobilization in monocytes, CXCL4 1162induces ROS formation, increases phagocytosis, and protects these cells from undergoing spontaneous apoptosis [1,2]. Furthermore, CXCL4 treatment provokes monocytes to express and to release several pro-inflammatory cytokines and chemokines [1,3], and stimulates the differentiation of these cells into a specific subtype of macrophages la...

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