The role of the sphingosine axis in immune regulation: A dichotomy in the anti-inflammatory effects between sphingosine kinase 1 and sphingosine kinase 2-dependent pathways
Background: Sphingosine kinase has been identified as playing a central role in the immune cascade, being a common mediator in the cellular response to a variety of signals. The different effects of sphingosine kinase 1 and 2 (SphK1 and SphK2, respectively) activity have not been completely characte...
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| description | Background: Sphingosine kinase has been identified as playing a central role in the immune cascade, being a common mediator in the cellular response to a variety of signals. The different effects of sphingosine kinase 1 and 2 (SphK1 and SphK2, respectively) activity have not been completely characterized. Aim: To determine the different roles played by SphK1 and SphK2 in the regulation of immune-mediated disorders. Methods: Nine groups of mice were studied. Concanavalin A (ConA) injection was used to induce immune-mediated hepatitis. Mice were treated with SphK1 inhibitor (termed SphK-I) and SphK2 inhibitor (termed ABC294640), prior to ConA injection, and effects of treatment on liver enzymes, subsets of T lymphocytes, and serum levels of cytokines were observed. Results: While liver enzyme elevation was ameliorated by administration of SphK1 inhibitor, SphK2 inhibitor-treated mice did not show this tendency. A marked decrease in expression of CD25+ T-cells and Foxp+ T-cells was observed in mice treated with a high dose of SphK1 inhibitor. Alleviation of liver damage was associated with a statistically significant reduction of serum IFNγ levels in mice treated with SphK1 inhibitor and not in those treated with SphK2 inhibitor. Conclusions: Early administration of SphK1 inhibitor in a murine model of immune-mediated hepatitis alleviated liver damage and inflammation with a statistically significant reduction in IFN-γ levels. The data support a dichotomy in the anti-inflammatory effects of SphK1 and SphK2, and suggests that isoenzyme-directed therapies can improve the effect of targeting these pathways. |
| doi_str_mv | 10.1177/20587384211053274 |
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The different effects of sphingosine kinase 1 and 2 (SphK1 and SphK2, respectively) activity have not been completely characterized. Aim: To determine the different roles played by SphK1 and SphK2 in the regulation of immune-mediated disorders. Methods: Nine groups of mice were studied. Concanavalin A (ConA) injection was used to induce immune-mediated hepatitis. Mice were treated with SphK1 inhibitor (termed SphK-I) and SphK2 inhibitor (termed ABC294640), prior to ConA injection, and effects of treatment on liver enzymes, subsets of T lymphocytes, and serum levels of cytokines were observed. Results: While liver enzyme elevation was ameliorated by administration of SphK1 inhibitor, SphK2 inhibitor-treated mice did not show this tendency. A marked decrease in expression of CD25+ T-cells and Foxp+ T-cells was observed in mice treated with a high dose of SphK1 inhibitor. Alleviation of liver damage was associated with a statistically significant reduction of serum IFNγ levels in mice treated with SphK1 inhibitor and not in those treated with SphK2 inhibitor. Conclusions: Early administration of SphK1 inhibitor in a murine model of immune-mediated hepatitis alleviated liver damage and inflammation with a statistically significant reduction in IFN-γ levels. The data support a dichotomy in the anti-inflammatory effects of SphK1 and SphK2, and suggests that isoenzyme-directed therapies can improve the effect of targeting these pathways.</description><identifier>ISSN: 2058-7384</identifier><identifier>ISSN: 0394-6320</identifier><identifier>EISSN: 2058-7384</identifier><identifier>DOI: 10.1177/20587384211053274</identifier><identifier>PMID: 34789044</identifier><language>eng</language><publisher>London, England: SAGE Publications</publisher><subject>Animal models ; Animals ; Anti-Inflammatory Agents - pharmacology ; Anti-Inflammatory Agents - therapeutic use ; CD25 antigen ; Concanavalin A ; Cytokines ; Hepatitis ; Hepatitis, Animal - blood ; Hepatitis, Animal - drug therapy ; Hepatitis, Animal - immunology ; Hepatitis, Animal - pathology ; Immunoregulation ; Inflammation ; Injection ; Interferon-gamma - blood ; Kinases ; Liver ; Liver - drug effects ; Liver - pathology ; Lymphocytes T ; Male ; Mice ; Mice, Inbred C57BL ; Original ; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors ; Phosphotransferases (Alcohol Group Acceptor) - immunology ; Serum levels ; Signal Transduction ; Sphingosine - immunology ; Sphingosine kinase ; Statistical analysis ; T-Lymphocyte Subsets - drug effects ; T-Lymphocyte Subsets - immunology ; γ-Interferon</subject><ispartof>International journal of immunopathology and pharmacology, 2021, Vol.35, p.20587384211053274-20587384211053274</ispartof><rights>The Author(s) 2021</rights><rights>The Author(s) 2021. This work is licensed under the Creative Commons Attribution – Non-Commercial License https://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2021 2021 SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c466t-4001b0e8121d66e856f4f5d9f66aed5f4ed1c0903f2d37f966a74371ec67dba13</citedby><cites>FETCH-LOGICAL-c466t-4001b0e8121d66e856f4f5d9f66aed5f4ed1c0903f2d37f966a74371ec67dba13</cites><orcidid>0000-0003-0802-1220</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645305/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645305/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,4010,21945,27830,27900,27901,27902,44921,45309,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34789044$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ishay, Yuval</creatorcontrib><creatorcontrib>Rotnemer-Golinkin, Dvorah</creatorcontrib><creatorcontrib>Ilan, Yaron</creatorcontrib><title>The role of the sphingosine axis in immune regulation: A dichotomy in the anti-inflammatory effects between sphingosine kinase 1 and sphingosine kinase 2-dependent pathways</title><title>International journal of immunopathology and pharmacology</title><addtitle>Int J Immunopathol Pharmacol</addtitle><description>Background: Sphingosine kinase has been identified as playing a central role in the immune cascade, being a common mediator in the cellular response to a variety of signals. The different effects of sphingosine kinase 1 and 2 (SphK1 and SphK2, respectively) activity have not been completely characterized. Aim: To determine the different roles played by SphK1 and SphK2 in the regulation of immune-mediated disorders. Methods: Nine groups of mice were studied. Concanavalin A (ConA) injection was used to induce immune-mediated hepatitis. Mice were treated with SphK1 inhibitor (termed SphK-I) and SphK2 inhibitor (termed ABC294640), prior to ConA injection, and effects of treatment on liver enzymes, subsets of T lymphocytes, and serum levels of cytokines were observed. Results: While liver enzyme elevation was ameliorated by administration of SphK1 inhibitor, SphK2 inhibitor-treated mice did not show this tendency. A marked decrease in expression of CD25+ T-cells and Foxp+ T-cells was observed in mice treated with a high dose of SphK1 inhibitor. Alleviation of liver damage was associated with a statistically significant reduction of serum IFNγ levels in mice treated with SphK1 inhibitor and not in those treated with SphK2 inhibitor. Conclusions: Early administration of SphK1 inhibitor in a murine model of immune-mediated hepatitis alleviated liver damage and inflammation with a statistically significant reduction in IFN-γ levels. The data support a dichotomy in the anti-inflammatory effects of SphK1 and SphK2, and suggests that isoenzyme-directed therapies can improve the effect of targeting these pathways.</description><subject>Animal models</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Anti-Inflammatory Agents - therapeutic use</subject><subject>CD25 antigen</subject><subject>Concanavalin A</subject><subject>Cytokines</subject><subject>Hepatitis</subject><subject>Hepatitis, Animal - blood</subject><subject>Hepatitis, Animal - drug therapy</subject><subject>Hepatitis, Animal - immunology</subject><subject>Hepatitis, Animal - pathology</subject><subject>Immunoregulation</subject><subject>Inflammation</subject><subject>Injection</subject><subject>Interferon-gamma - blood</subject><subject>Kinases</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - pathology</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Original</subject><subject>Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors</subject><subject>Phosphotransferases (Alcohol Group Acceptor) - immunology</subject><subject>Serum levels</subject><subject>Signal Transduction</subject><subject>Sphingosine - immunology</subject><subject>Sphingosine kinase</subject><subject>Statistical analysis</subject><subject>T-Lymphocyte Subsets - drug effects</subject><subject>T-Lymphocyte Subsets - immunology</subject><subject>γ-Interferon</subject><issn>2058-7384</issn><issn>0394-6320</issn><issn>2058-7384</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>AFRWT</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kstu1TAQhi0EotWhD8AGWWLDJsW32AkLpKriJlViU9aWTzw-cUnsEDst5514SBydUlouK49nvv_3jMYIPafklFKlXjNSN4o3glFKas6UeISO11y1Jh_fi4_QSUpXhBBKuKgb-hQdcaGalghxjH5c9oDnOACODucSp6n3YReTD4DNd5-wD9iP41KuM-yWwWQfwxt8hq3v-pjjuF-JVWlC9pUPbjDjaHKc9xicgy4nvIV8AxAeeH_1wSTAtMjsvwqssjBBsBAynkzub8w-PUNPnBkSnNyeG_Tl_bvL84_VxecPn87PLqpOSJkrUUbdEmgoo1ZKaGrphKtt66Q0YGsnwNKOtIQ7ZrlybUkrwRWFTiq7NZRv0NuD77RsR7Bd6WE2g55mP5p5r6Px-mEl-F7v4rVupKh52cYGvbo1mOO3BVLWo08dDIMJEJekWd22REkiVvTlH-hVXOZQxtNMUs4a1nJWKHqgujmmNIO7a4YSvX4H_dd3KJoX96e4U_xafgFOD0AyO_j97P8dfwKg88Cq</recordid><startdate>2021</startdate><enddate>2021</enddate><creator>Ishay, Yuval</creator><creator>Rotnemer-Golinkin, Dvorah</creator><creator>Ilan, Yaron</creator><general>SAGE Publications</general><general>Sage Publications Ltd</general><scope>AFRWT</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0802-1220</orcidid></search><sort><creationdate>2021</creationdate><title>The role of the sphingosine axis in immune regulation: A dichotomy in the anti-inflammatory effects between sphingosine kinase 1 and sphingosine kinase 2-dependent pathways</title><author>Ishay, Yuval ; Rotnemer-Golinkin, Dvorah ; Ilan, Yaron</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c466t-4001b0e8121d66e856f4f5d9f66aed5f4ed1c0903f2d37f966a74371ec67dba13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Anti-Inflammatory Agents - therapeutic use</topic><topic>CD25 antigen</topic><topic>Concanavalin A</topic><topic>Cytokines</topic><topic>Hepatitis</topic><topic>Hepatitis, Animal - blood</topic><topic>Hepatitis, Animal - drug therapy</topic><topic>Hepatitis, Animal - immunology</topic><topic>Hepatitis, Animal - pathology</topic><topic>Immunoregulation</topic><topic>Inflammation</topic><topic>Injection</topic><topic>Interferon-gamma - blood</topic><topic>Kinases</topic><topic>Liver</topic><topic>Liver - drug effects</topic><topic>Liver - pathology</topic><topic>Lymphocytes T</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Original</topic><topic>Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors</topic><topic>Phosphotransferases (Alcohol Group Acceptor) - immunology</topic><topic>Serum levels</topic><topic>Signal Transduction</topic><topic>Sphingosine - immunology</topic><topic>Sphingosine kinase</topic><topic>Statistical analysis</topic><topic>T-Lymphocyte Subsets - drug effects</topic><topic>T-Lymphocyte Subsets - immunology</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ishay, Yuval</creatorcontrib><creatorcontrib>Rotnemer-Golinkin, Dvorah</creatorcontrib><creatorcontrib>Ilan, Yaron</creatorcontrib><collection>Sage Journals GOLD Open Access 2024</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of immunopathology and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ishay, Yuval</au><au>Rotnemer-Golinkin, Dvorah</au><au>Ilan, Yaron</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The role of the sphingosine axis in immune regulation: A dichotomy in the anti-inflammatory effects between sphingosine kinase 1 and sphingosine kinase 2-dependent pathways</atitle><jtitle>International journal of immunopathology and pharmacology</jtitle><addtitle>Int J Immunopathol Pharmacol</addtitle><date>2021</date><risdate>2021</risdate><volume>35</volume><spage>20587384211053274</spage><epage>20587384211053274</epage><pages>20587384211053274-20587384211053274</pages><issn>2058-7384</issn><issn>0394-6320</issn><eissn>2058-7384</eissn><abstract>Background: Sphingosine kinase has been identified as playing a central role in the immune cascade, being a common mediator in the cellular response to a variety of signals. The different effects of sphingosine kinase 1 and 2 (SphK1 and SphK2, respectively) activity have not been completely characterized. Aim: To determine the different roles played by SphK1 and SphK2 in the regulation of immune-mediated disorders. Methods: Nine groups of mice were studied. Concanavalin A (ConA) injection was used to induce immune-mediated hepatitis. Mice were treated with SphK1 inhibitor (termed SphK-I) and SphK2 inhibitor (termed ABC294640), prior to ConA injection, and effects of treatment on liver enzymes, subsets of T lymphocytes, and serum levels of cytokines were observed. Results: While liver enzyme elevation was ameliorated by administration of SphK1 inhibitor, SphK2 inhibitor-treated mice did not show this tendency. A marked decrease in expression of CD25+ T-cells and Foxp+ T-cells was observed in mice treated with a high dose of SphK1 inhibitor. Alleviation of liver damage was associated with a statistically significant reduction of serum IFNγ levels in mice treated with SphK1 inhibitor and not in those treated with SphK2 inhibitor. Conclusions: Early administration of SphK1 inhibitor in a murine model of immune-mediated hepatitis alleviated liver damage and inflammation with a statistically significant reduction in IFN-γ levels. The data support a dichotomy in the anti-inflammatory effects of SphK1 and SphK2, and suggests that isoenzyme-directed therapies can improve the effect of targeting these pathways.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><pmid>34789044</pmid><doi>10.1177/20587384211053274</doi><orcidid>https://orcid.org/0000-0003-0802-1220</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of immunopathology and pharmacology, 2021, Vol.35, p.20587384211053274-20587384211053274 |
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| subjects | Animal models Animals Anti-Inflammatory Agents - pharmacology Anti-Inflammatory Agents - therapeutic use CD25 antigen Concanavalin A Cytokines Hepatitis Hepatitis, Animal - blood Hepatitis, Animal - drug therapy Hepatitis, Animal - immunology Hepatitis, Animal - pathology Immunoregulation Inflammation Injection Interferon-gamma - blood Kinases Liver Liver - drug effects Liver - pathology Lymphocytes T Male Mice Mice, Inbred C57BL Original Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors Phosphotransferases (Alcohol Group Acceptor) - immunology Serum levels Signal Transduction Sphingosine - immunology Sphingosine kinase Statistical analysis T-Lymphocyte Subsets - drug effects T-Lymphocyte Subsets - immunology γ-Interferon |
| title | The role of the sphingosine axis in immune regulation: A dichotomy in the anti-inflammatory effects between sphingosine kinase 1 and sphingosine kinase 2-dependent pathways |
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