Sphingosine kinase 1 is essential for proteinase-activated receptor-1 signalling in epithelial and endothelial cells |
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Authors: | Andreas Billich Nicole Urtz Roland Reuschel Thomas Baumruker |
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Affiliation: | 1. Department of Neurology, Cedars-Sinai Medical Center, Los Angeles 90048, USA;2. McKinsey & Company, Beijing, China;3. Department of Surgery, Division of Trauma and Critical Care, Cedars-Sinai Medical Center, Los Angeles 90048, USA;1. Department of Electrical Engineering, Dr. B C Roy Engineering College, Durgapur, West Bengal, India;2. Department of Electrical Engineering, Jalpaiguri Government Engineering College, Jalpaiguri-735102, West Bengal, India;3. Department of Information Technology, National Institute of Technology, Durgapur, West Bengal, India;1. Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu, India;2. Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India;3. Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India;1. Key Lab for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China;2. Oral Histopathology Department, School and Hospital of Stomatology, Wuhan University, Wuhan, China;3. Wuxi Stomatology Hospital, Wuxi, China |
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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 PGE2. 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 NFκB, 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. |
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