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Sphingosine kinase 1 is essential for proteinase-activated receptor-1 signalling in epithelial and endothelial cells.
Int J Biochem Cell Biol. 2009 Jul; 41(7):1547-55.IJ

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.

Authors+Show Affiliations

Novartis Institutes for BioMedical Research, Brunnerstrasse 59, Vienna, Austria. andreas.billich@novartis.comNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19162217

Citation

Billich, Andreas, et al. "Sphingosine Kinase 1 Is Essential for Proteinase-activated Receptor-1 Signalling in Epithelial and Endothelial Cells." The International Journal of Biochemistry & Cell Biology, vol. 41, no. 7, 2009, pp. 1547-55.
Billich A, Urtz N, Reuschel R, et al. Sphingosine kinase 1 is essential for proteinase-activated receptor-1 signalling in epithelial and endothelial cells. Int J Biochem Cell Biol. 2009;41(7):1547-55.
Billich, A., Urtz, N., Reuschel, R., & Baumruker, T. (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), 1547-55. https://doi.org/10.1016/j.biocel.2009.01.001
Billich A, et al. Sphingosine Kinase 1 Is Essential for Proteinase-activated Receptor-1 Signalling in Epithelial and Endothelial Cells. Int J Biochem Cell Biol. 2009;41(7):1547-55. PubMed PMID: 19162217.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sphingosine kinase 1 is essential for proteinase-activated receptor-1 signalling in epithelial and endothelial cells. AU - Billich,Andreas, AU - Urtz,Nicole, AU - Reuschel,Roland, AU - Baumruker,Thomas, Y1 - 2009/01/08/ PY - 2008/11/09/received PY - 2008/12/24/revised PY - 2009/01/05/accepted PY - 2009/1/24/entrez PY - 2009/1/24/pubmed PY - 2009/6/11/medline SP - 1547 EP - 55 JF - The international journal of biochemistry & cell biology JO - Int J Biochem Cell Biol VL - 41 IS - 7 N2 - 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. SN - 1878-5875 UR - https://www.unboundmedicine.com/medline/citation/19162217/Sphingosine_kinase_1_is_essential_for_proteinase_activated_receptor_1_signalling_in_epithelial_and_endothelial_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1357-2725(09)00007-7 DB - PRIME DP - Unbound Medicine ER -