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Sphingosine kinase 1 is essential for proteinase-activated receptor-1 signalling in epithelial and endothelial cells.

Billich, Andreas and Urtz, Nicole and Reuschel, Roland and Baumruker, Thomas (2009) Sphingosine kinase 1 is essential for proteinase-activated receptor-1 signalling in epithelial and endothelial cells. The International Journal of Biochemistry & Cell Biology, 41 (7). pp. 1547-1555. ISSN 1878-5875

Abstract

There is accumulating evidence that activation of sphingosine kinase 1 (SPHK1) is an important element in intracellular signalling cascades initiated by stimulation of multiple receptors, including certain growth factor, cytokine, and also G-protein coupled receptors. We here report that stimulation of the lung epithelial cell line A549 by thrombin leads to transient increase of SPHK1 activity and elevation of intracellular sphingosine-1-phosphate (S1P); abrogation of this stimulation by SPHK1-specific siRNA, pharmacological inhibition, or expression of a dominant-negative SPHK1 mutant blocks the response to thrombin, as measured by secretion of MCP-1, IL-6, IL-8, and PGE(2). Using selective stimulation of proteinase-activated receptors (PARs) a specific involvement of SPHK1 in the PAR-1 induced responses in A549 cell, including activation of NFkappaB, was evident, while PAR-2 and PAR-4 responses were independent of SPHK1. Moreover, PAR-1 or thrombin-induced cytokine production and adhesion factor expression of human umbilical vein endothelial cells was also seen to depend on SPHK1. Using dermal microvascular endothelial cells from SPHK1-deficient mice, we showed that absence of the enzyme abrogates MCP-1 production induced in these cells upon treatment with thrombin or PAR-1 activating peptide. We propose SPHK1 inhibition as a novel way to block PAR-1 mediated signalling, which could be useful in treatment of a number of diseases, in particular in atherosclerosis.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: Proteinase-activated receptor; Sphingosine kinase; Sphingosine-1-phosphate; Thrombin
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Date Deposited: 14 Dec 2009 13:48
Last Modified: 31 Jan 2013 00:54
URI: https://oak.novartis.com/id/eprint/1440

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