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Your search keyword '"Alvarez, Sergio E."' showing total 4 results
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4 results on '"Alvarez, Sergio E."'

1. Activation of Sphingosine Kinase 1.

Author

Hirabayashi, Yoshio, Igarashi, Yasuyuki, Merrill, Alfred H., Maceyka, Michael, Alvarez, Sergio E., Milstien, Sheldon, and Spiegel, Sarah

Abstract

Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that regulates many important biological processes as a ligand for cell surface receptors and as an intracellular second messenger. S1P levels inside cells are regulated in a temporal and spatial manner by the balance between its formation, catalyzed by two sphingosine kinase isoenzymes, SphK1 and SphK2, and degradation by S1P lyase and S1P-specific phosphatases. Activation of SphK1 is a key step in the agonist-induced regulation of S1P levels. SphK1 is a cytosolic enzyme and a growing body of evidence suggests that S1P production is also regulated by the translocation of SphK1 to membranes, where its substrate sphingosine is formed. SphK1 translocation to membranes can be mediated by interactions with lipids and proteins. Here we review the current knowledge of SphK1 activation and translocation. [ABSTRACT FROM AUTHOR]

Published
2006
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2. Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions

Author

Oskeritzian, Carole A., Alvarez, Sergio E., Hait, Nitai C., Price, Megan M., Milstien, Sheldon, and Spiegel, Sarah

Abstract

Sphingosine-1-phosphate (S1P) is now emerging as a potent lipid mediator produced by mast cells that contributes to inflammatory and allergic responses. In contrast to its weak effect on degranulation of murine mast cells, S1P potently induced degranulation of the human LAD2 mast-cell line and cord blood–derived human mast cells (hMCs). S1P also stimulated production and secretion of cytokines, TNF-α and IL-6, and markedly enhanced secretion of a chemokine, CCL2/MCP-1, important modulators of inflammation. S1P is produced in mast cells by the 2 sphingosine kinases, SphK1 and SphK2. SphK1 but not SphK2 plays a critical role in IgE/Ag-induced degranulation, migration toward antigen, and CCL2 secretion from hMCs, as determined by specifically down-regulating their expression. However, both isoenzymes were required for efficient TNF-α secretion. Taken together, our data suggest that differential formation of S1P by SphK1 and SphK2 has distinct and important actions in hMCs.

Published
2008
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3. Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions

Author

Oskeritzian, Carole A., Alvarez, Sergio E., Hait, Nitai C., Price, Megan M., Milstien, Sheldon, and Spiegel, Sarah

Abstract

Sphingosine-1-phosphate (S1P) is now emerging as a potent lipid mediator produced by mast cells that contributes to inflammatory and allergic responses. In contrast to its weak effect on degranulation of murine mast cells, S1P potently induced degranulation of the human LAD2 mast-cell line and cord blood–derived human mast cells (hMCs). S1P also stimulated production and secretion of cytokines, TNF-α and IL-6, and markedly enhanced secretion of a chemokine, CCL2/MCP-1, important modulators of inflammation. S1P is produced in mast cells by the 2 sphingosine kinases, SphK1 and SphK2. SphK1 but not SphK2 plays a critical role in IgE/Ag-induced degranulation, migration toward antigen, and CCL2 secretion from hMCs, as determined by specifically down-regulating their expression. However, both isoenzymes were required for efficient TNF-α secretion. Taken together, our data suggest that differential formation of S1P by SphK1 and SphK2 has distinct and important actions in hMCs.

Published
2008
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4. A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell–dependent murine model of allergic asthma.

Author

Price, Megan M., Oskeritzian, Carole A., Falanga, Yves T., Harikumar, Kuzhuvelil B., Allegood, Jeremy C., Alvarez, Sergio E., Conrad, Daniel, Ryan, John J., Milstien, Sheldon, and Spiegel, Sarah

Subjects
SPHINGOSINE-1-phosphate, MAST cell physiology, ISOENZYMES, RESPIRATORY diseases, ASTHMA, KNOCKOUT mice
Abstract

Background: Sphingosine-1-phosphate (S1P), which is produced by 2 sphingosine kinase (SphK) isoenzymes, SphK1 and SphK2, has been implicated in IgE-mediated mast cell responses. However, studies of allergic inflammation in isotype-specific SphK knockout mice have not clarified their contribution, and the role that S1P plays in vivo in a mast cell– and IgE-dependent murine model of allergic asthma has not yet been examined. Objective: We used an isoenzyme-specific SphK1 inhibitor, SK1-I, to investigate the contributions of S1P and SphK1 to mast cell–dependent airway hyperresponsiveness (AHR) and airway inflammation in mice. Methods: Allergic airway inflammation and AHR were examined in a mast cell–dependent murine model of ovalbumin (OVA)–induced asthma. C57BL/6 mice received intranasal delivery of SK1-I before sensitization and challenge with OVA or only before challenge. Results: SK1-I inhibited antigen-dependent activation of human and murine mast cells and suppressed activation of nuclear factor κB (NF-κB), a master transcription factor that regulates the expression of proinflammatory cytokines. SK1-I treatment of mice sensitized to OVA in the absence of adjuvant, in which mast cell–dependent allergic inflammation develops, significantly reduced OVA-induced AHR to methacholine; decreased numbers of eosinophils and levels of the cytokines IL-4, IL-5, IL-6, IL-13, IFN-γ, and TNF-α and the chemokines eotaxin and CCL2 in bronchoalveolar lavage fluid; and decreased pulmonary inflammation, as well as activation of NF-κB in the lungs. Conclusion: S1P and SphK1 play important roles in mast cell–dependent, OVA-induced allergic inflammation and AHR, in part by regulating the NF-κB pathway. [Copyright &y& Elsevier]

Published
2013
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