{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T04:59:52Z","timestamp":1769662792100,"version":"3.49.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2009,7,1]],"date-time":"2009-07-01T00:00:00Z","timestamp":1246406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mast cell degranulation is pivotal to allergic diseases; investigating novel pathways triggering mast cell degranulation would undoubtedly have important therapeutic potential. Fc\u03b5RI-mediated degranulation has contradictorily been shown to require SphK1 or SphK2, depending on the reports. We investigated the in vitro and in vivo specific role(s) of SphK1 and SphK2 in Fc\u03b5RI-mediated responses, using specific small interfering RNA-gene silencing. The small interfering RNA-knockdown of SphK1 in mast cells inhibited several signaling mechanisms and effector functions, triggered by Fc\u03b5RI stimulation including: Ca2+ signals, NF\u03baB activation, degranulation, cytokine\/chemokine, and eicosanoid production, whereas silencing SphK2 had no effect at all. Moreover, silencing SPHK1 in vivo, in different strains of mice, strongly inhibited mast cell-mediated anaphylaxis, including inhibition of vascular permeability, tissue mast cell degranulation, changes in temperature, and serum histamine and cytokine levels, whereas silencing SPHK2 had no effect and the mice developed anaphylaxis. Our data differ from a recent report using SPHK1\u2212\/\u2212 and SPHK2\u2212\/\u2212 mice, which showed that SphK2 was required for Fc\u03b5RI-mediated mast cell responses. We performed experiments in mast cells derived from SPHK1\u2212\/\u2212 and SPHK2\u2212\/\u2212 mice and show that the calcium response and degranulation, triggered by Fc\u03b5RI-cross-linking, is not different from that triggered in wild-type cells. Moreover, IgE-mediated anaphylaxis in the knockout mice showed similar levels in temperature changes and serum histamine to that from wild-type mice, indicating that there was no protection from anaphylaxis for either knockout mice. Thus, our data strongly suggest a previously unrecognized compensatory mechanism in the knockout mice, and establishes a role for SphK1 in IgE-mediated mast cell responses.<\/jats:p>","DOI":"10.4049\/jimmunol.0803430","type":"journal-article","created":{"date-parts":[[2009,6,19]],"date-time":"2009-06-19T17:04:08Z","timestamp":1245431048000},"page":"221-227","source":"Crossref","is-referenced-by-count":28,"title":["Sphingosine Kinase1 Is Pivotal for Fc\u03b5RI-Mediated Mast Cell Signaling and Functional Responses In Vitro and In Vivo"],"prefix":"10.1093","volume":"183","author":[{"given":"Peter N","family":"Pushparaj","sequence":"first","affiliation":[{"name":"Medicine-Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow , Glasgow, Scotland,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jayapal","family":"Manikandan","sequence":"additional","affiliation":[{"name":"Department of Physiology, Yong Loo Lim School of Medicine, National University of Singapore ,","place":["Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hwee Kee","family":"Tay","sequence":"additional","affiliation":[{"name":"Medicine-Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow , Glasgow, Scotland,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiau Chen","family":"H'ng","sequence":"additional","affiliation":[{"name":"Department of Physiology, Yong Loo Lim School of Medicine, National University of Singapore ,","place":["Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srinivasan D","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Yong Loo Lim School of Medicine, National University of Singapore ,","place":["Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josef","family":"Pfeilschifter","sequence":"additional","affiliation":[{"name":"Pharmazentrum Frankfurt\/Zentrum f\u00fcr Arzneimittelforschung, Entwicklung und Sicherheit, University Hospital , Frankfurt am Main,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Huwiler","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, University of Bern , Bern,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alirio J","family":"Melendez","sequence":"additional","affiliation":[{"name":"Medicine-Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow , Glasgow, Scotland,","place":["United Kingdom"]},{"name":"Department of Physiology, Yong Loo Lim School of Medicine, National University of Singapore ,","place":["Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,7,1]]},"reference":[{"key":"2026012811263836300_R1","first-page":"21","article-title":"The two faces of the mast cell.","volume-title":"Nature","year":"1996"},{"key":"2026012811263836300_R2","first-page":"749","article-title":"Mast cells as \u201ctunable\u201d effector and immunoregulatory cells: recent advances.","volume-title":"Annu. Rev. Immunol.","year":"2005"},{"key":"2026012811263836300_R3","first-page":"93","article-title":"Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data.","volume-title":"Nat. Rev. Immunol.","year":"2007"},{"key":"2026012811263836300_R4","first-page":"634","article-title":"Calcium mobilization via sphingosine kinase in signalling by the Fc\u03b5RI antigen receptor.","volume-title":"Nature","year":"1996"},{"key":"2026012811263836300_R5","first-page":"34","article-title":"Molecular diversity of sphingolipid signalling.","volume-title":"FEBS Lett.","year":"1997"},{"key":"2026012811263836300_R6","first-page":"1","article-title":"The balance between sphingosine and sphingosine-1-phosphate is decisive for mast cell activation after Fc\u03b5 receptor I triggering.","volume-title":"J. Exp. Med.","year":"1999"},{"key":"2026012811263836300_R7","first-page":"193","article-title":"Sphingosine-1-phosphate inhibits PDGF-induced chemotaxis of human arterial smooth muscle cells: spatial and temporal modulation of PDGF chemotactic signal transduction.","volume-title":"J. Cell Biol.","year":"1995"},{"key":"2026012811263836300_R8","first-page":"57","article-title":"Sphingolipids and the regulation of the immune response.","volume-title":"Semin. Immunol.","year":"2002"},{"key":"2026012811263836300_R9","first-page":"1212","article-title":"Sphingosine 1-phosphate modulates human airway smooth muscle cell functions that promote inflammation and airway remodeling in asthma.","volume-title":"FASEB J.","year":"2001"},{"key":"2026012811263836300_R10","first-page":"390","article-title":"Sphingosine-1-phosphate in allergic responses, asthma and anaphylaxis.","volume-title":"Pharmacol. Ther.","year":"2007"},{"key":"2026012811263836300_R11","first-page":"17255","article-title":"Dichotomy of Ca2+ signals triggered by different phospholipid pathways in antigen stimulation of human mast cells.","volume-title":"J. Biol. Chem.","year":"2002"},{"key":"2026012811263836300_R12","first-page":"959","article-title":"Transactivation of sphingosine-1-phosphate receptors by Fc\u03b5RI triggering is required for normal mast cell degranulation and chemotaxis.","volume-title":"J. Exp. Med.","year":"2004"},{"key":"2026012811263836300_R13","first-page":"1375","article-title":"Inhibition of Fc\u03b5RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes.","volume-title":"Nat. Med.","year":"2007"},{"key":"2026012811263836300_R14","first-page":"210","article-title":"Genome-wide gene expression profiling of human mast cells stimulated by IgE or Fc\u03b5RI-aggregation reveals a complex network of genes involved in inflammatory responses.","volume-title":"BMC Genomics","year":"2006"},{"key":"2026012811263836300_R15","first-page":"287","article-title":"The sphingosine kinase-sphingosine-1-phosphate axis is a determinant of mast cell function and anaphylaxis.","volume-title":"Immunity","year":"2007"},{"key":"2026012811263836300_R16","first-page":"4193","article-title":"Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions.","volume-title":"Blood","year":"2008"},{"key":"2026012811263836300_R17","first-page":"6465","article-title":"Peritoneal cell-derived mast cells: an in vitro model of mature serosal-type mouse mast cells.","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012811263836300_R18","first-page":"109","article-title":"Sphingosine kinase 1 regulates pro-inflammatory responses triggered by TNF\u03b1 in primary human monocytes.","volume-title":"J. Cell Physiol.","year":"2006"},{"key":"2026012811263836300_R19","first-page":"1817","article-title":"Refining siRNA in vivo transfection: Silencing SPHK1 reveals its key role in C5a-induced inflammation in vivo.","volume-title":"Int. J. Biochem. Cell Biol.","year":"2008"},{"key":"2026012811263836300_R20","first-page":"1375","article-title":"Role of mast cells in anaphylaxis: evidence for the importance of mast cells in the cardiopulmonary alterations and death induced by anti-IgE in mice.","volume-title":"J. Clin. Invest.","year":"1989"},{"key":"2026012811263836300_R21","first-page":"1699","article-title":"Mast-cell infiltration of airway smooth muscle in asthma.","volume-title":"N. Engl. J. Med.","year":"2002"},{"key":"2026012811263836300_R22","first-page":"969","article-title":"Abolition of anaphylaxis by targeted disruption of the high affinity immunoglobulin E receptor \u03b1 chain gene.","volume-title":"Cell","year":"1993"},{"key":"2026012811263836300_R23","first-page":"266","article-title":"The ins and outs of IgE-dependent mast-cell exocytosis.","volume-title":"Trends Immunol.","year":"2004"},{"key":"2026012811263836300_R24","first-page":"931","article-title":"The high-affinity IgE receptor (Fc\u03b5RI): from physiology to pathology.","volume-title":"Annu. Rev. Immunol.","year":"1999"},{"key":"2026012811263836300_R25","first-page":"500","article-title":"Dependence of mast cell IgE-mediated cytokine production on nuclear factor-\u03baB activity.","volume-title":"J. Allergy Clin. Immunol.","year":"2000"},{"key":"2026012811263836300_R26","first-page":"4391","article-title":"IL-9 and IL-13 production by activated mast cells is strongly enhanced in the presence of lipopolysaccharide: NF-\u03baB is decisively involved in the expression of IL-9.","volume-title":"J. Immunol.","year":"2001"},{"key":"2026012811263836300_R27","first-page":"3801","article-title":"Th2 cytokine production from mast cells is directly induced by lipopolysaccharide and distinctly regulated by c-Jun N-terminal kinase and p38 pathways.","volume-title":"J. Immunol.","year":"2002"},{"key":"2026012811263836300_R28","first-page":"933","article-title":"Calcium oscillations increase the efficiency and specificity of gene expression.","volume-title":"Nature","year":"1998"},{"key":"2026012811263836300_R29","first-page":"91","article-title":"Appearances can be deceiving: phenotypes of knockout mice.","volume-title":"Brief Funct. Genomic Proteomic.","year":"2007"},{"key":"2026012811263836300_R30","first-page":"63","article-title":"Induced gene expression in human brain after the split from chimpanzee.","volume-title":"Trends Genet.","year":"2003"},{"key":"2026012811263836300_R31","first-page":"354","article-title":"Evolution of duplicate genes versus genetic robustness against null mutations.","volume-title":"Trends Genet.","year":"2003"},{"key":"2026012811263836300_R32","first-page":"295","article-title":"Transcription control reprogramming in genetic backup circuits.","volume-title":"Nat. Genet.","year":"2005"},{"key":"2026012811263836300_R33","first-page":"167","article-title":"Evolution of genetic redundancy.","volume-title":"Nature","year":"1997"},{"key":"2026012811263836300_R34","first-page":"56","article-title":"Normal neutrophil functions in sphingosine kinase type 1 and 2 knockout mice.","volume-title":"Immunol. Lett.","year":"2007"},{"key":"2026012811263836300_R35","first-page":"11113","article-title":"Essential role for sphingosine kinases in neural and vascular development.","volume-title":"Mol. Cell Biol.","year":"2005"},{"key":"2026012811263836300_R36","first-page":"624","article-title":"Roles of mast cells and basophils in innate and acquired immunity.","volume-title":"Curr. Opin. 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