Proteomic analysis of cholera toxin adjuvant-stimulated human monocytes identifies Thrombospondin-1 and Integrin-β1 as strongly upregulated molecules involved in adjuvant activity
Cholera Toxin (CT) as well as its related non-toxic mmCT and dmLT mutant proteins have been shown to be potent adjuvants for mucosally administered vaccines. Their adjuvant activity involves activation of cAMP/protein kinase A (PKA) signaling and inflammasome/IL-1β pathways in antigen presenting cel...
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| Veröffentlicht in: | Scientific reports 2019-02, Vol.9 (1), p.2812-2812, Article 2812 |
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| creator | Terrinoni, Manuela Holmgren, Jan Lebens, Michael Larena, Maximilian |
| description | Cholera Toxin (CT) as well as its related non-toxic mmCT and dmLT mutant proteins have been shown to be potent adjuvants for mucosally administered vaccines. Their adjuvant activity involves activation of cAMP/protein kinase A (PKA) signaling and inflammasome/IL-1β pathways in antigen presenting cells (APC). To get a further understanding of the signal transduction and downstream pathways activated in APCs by this group of adjuvants we have, employing quantitative proteomic analytic tools, investigated human monocytes at various time points after treatment with CT. We report the activation of three main biological pathways among upregulated proteins, peaking at 16 hours of CT treatment: cellular organization, metabolism, and immune response. Specifically, in the further analyzed immune response pathway we note a strong upregulation of thrombospondin 1 (THBS1) and integrin β1 (ITGB1) in response to CT as well as to mmCT and dmLT, mediated via cAMP/PKA and NFKB signaling. Importantly, inhibition
in vitro
of THSB1 and ITGB1 in monocytes or primary dendritic cells using siRNA abrogated the ability of the treated APCs to promote an adjuvant-stimulated Th17 cell response when co-cultured with peripheral blood lymphocytes indicating the involvement of these molecules in the adjuvant action on APCs by CT, mmCT and dmLT. |
| doi_str_mv | 10.1038/s41598-019-38726-0 |
| format | Article |
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in vitro
of THSB1 and ITGB1 in monocytes or primary dendritic cells using siRNA abrogated the ability of the treated APCs to promote an adjuvant-stimulated Th17 cell response when co-cultured with peripheral blood lymphocytes indicating the involvement of these molecules in the adjuvant action on APCs by CT, mmCT and dmLT.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-019-38726-0</identifier><identifier>PMID: 30808871</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>101/47 ; 13/31 ; 38/89 ; 631/250/590 ; 631/80/86 ; 82/80 ; Adjuvants ; Antigen-presenting cells ; Cholera ; Cholera toxin ; Cyclic AMP ; Dendritic cells ; Helper cells ; Humanities and Social Sciences ; IL-1β ; Immune response ; Inflammasomes ; Kinases ; Lymphocytes ; Lymphocytes T ; Monocytes ; multidisciplinary ; NF-κB protein ; Peripheral blood ; Protein kinase A ; Science ; Science (multidisciplinary) ; Signal transduction ; siRNA ; Thrombospondin ; Toxins ; Waterborne diseases</subject><ispartof>Scientific reports, 2019-02, Vol.9 (1), p.2812-2812, Article 2812</ispartof><rights>The Author(s) 2019</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-f0025369eb6d97e70c6c4f7380fb32da8a28c7993d0f43c46aad28320a59c8563</citedby><cites>FETCH-LOGICAL-c474t-f0025369eb6d97e70c6c4f7380fb32da8a28c7993d0f43c46aad28320a59c8563</cites><orcidid>0000-0002-8799-7645</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/PMC6391456/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391456/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41099,42168,51554,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30808871$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Terrinoni, Manuela</creatorcontrib><creatorcontrib>Holmgren, Jan</creatorcontrib><creatorcontrib>Lebens, Michael</creatorcontrib><creatorcontrib>Larena, Maximilian</creatorcontrib><title>Proteomic analysis of cholera toxin adjuvant-stimulated human monocytes identifies Thrombospondin-1 and Integrin-β1 as strongly upregulated molecules involved in adjuvant activity</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Cholera Toxin (CT) as well as its related non-toxic mmCT and dmLT mutant proteins have been shown to be potent adjuvants for mucosally administered vaccines. Their adjuvant activity involves activation of cAMP/protein kinase A (PKA) signaling and inflammasome/IL-1β pathways in antigen presenting cells (APC). To get a further understanding of the signal transduction and downstream pathways activated in APCs by this group of adjuvants we have, employing quantitative proteomic analytic tools, investigated human monocytes at various time points after treatment with CT. We report the activation of three main biological pathways among upregulated proteins, peaking at 16 hours of CT treatment: cellular organization, metabolism, and immune response. Specifically, in the further analyzed immune response pathway we note a strong upregulation of thrombospondin 1 (THBS1) and integrin β1 (ITGB1) in response to CT as well as to mmCT and dmLT, mediated via cAMP/PKA and NFKB signaling. Importantly, inhibition
in vitro
of THSB1 and ITGB1 in monocytes or primary dendritic cells using siRNA abrogated the ability of the treated APCs to promote an adjuvant-stimulated Th17 cell response when co-cultured with peripheral blood lymphocytes indicating the involvement of these molecules in the adjuvant action on APCs by CT, mmCT and dmLT.</description><subject>101/47</subject><subject>13/31</subject><subject>38/89</subject><subject>631/250/590</subject><subject>631/80/86</subject><subject>82/80</subject><subject>Adjuvants</subject><subject>Antigen-presenting cells</subject><subject>Cholera</subject><subject>Cholera toxin</subject><subject>Cyclic AMP</subject><subject>Dendritic cells</subject><subject>Helper cells</subject><subject>Humanities and Social Sciences</subject><subject>IL-1β</subject><subject>Immune response</subject><subject>Inflammasomes</subject><subject>Kinases</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Monocytes</subject><subject>multidisciplinary</subject><subject>NF-κB protein</subject><subject>Peripheral blood</subject><subject>Protein kinase A</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signal transduction</subject><subject>siRNA</subject><subject>Thrombospondin</subject><subject>Toxins</subject><subject>Waterborne diseases</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kstu1DAUhiMEolXpC7BAltiwCfgWx94goYpLpUqwKGvL4zgZjxx7sJ2oeS3Ec_BMeJqhDCzwxsfn_Oc7tvxX1XMEXyNI-JtEUSN4DZGoCW8xq-Gj6hxD2tSYYPz4JD6rLlPawbIaLCgST6szAjnkvEXn1Y8vMWQTRquB8sotySYQeqC3wZmoQA531gPV7aZZ-VynbMfJqWw6sJ1G5cEYfNBLNgnYzvhse1vC220M4yakffCd9TUq5A5c-2yGWI4_v5dEAinH4Ae3gGkfzXCEjmWqntwB5-fg5pI6GQ-Uzna2eXlWPemVS-byuF9UXz-8v736VN98_nh99e6m1rSlue4hxA1hwmxYJ1rTQs007VvCYb8huFNcYa5bIUgHe0o0ZUp1mBMMVSM0bxi5qN6u3P20GU2nywujcnIf7ajiIoOy8u-Kt1s5hFkyIhC9B7w6AmL4NpmU5WiTNs4pb8KUJEacMcw4okX68h_pLkyxfMmqQg2l7ADEq0rHkFI0_cNlEJQHX8jVF7L4Qt77QsLS9OL0GQ8tv11QBGQVpFLyg4l_Zv8H-wvrH8nv</recordid><startdate>20190226</startdate><enddate>20190226</enddate><creator>Terrinoni, Manuela</creator><creator>Holmgren, Jan</creator><creator>Lebens, Michael</creator><creator>Larena, Maximilian</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8799-7645</orcidid></search><sort><creationdate>20190226</creationdate><title>Proteomic analysis of cholera toxin adjuvant-stimulated human monocytes identifies Thrombospondin-1 and Integrin-β1 as strongly upregulated molecules involved in adjuvant activity</title><author>Terrinoni, Manuela ; 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Their adjuvant activity involves activation of cAMP/protein kinase A (PKA) signaling and inflammasome/IL-1β pathways in antigen presenting cells (APC). To get a further understanding of the signal transduction and downstream pathways activated in APCs by this group of adjuvants we have, employing quantitative proteomic analytic tools, investigated human monocytes at various time points after treatment with CT. We report the activation of three main biological pathways among upregulated proteins, peaking at 16 hours of CT treatment: cellular organization, metabolism, and immune response. Specifically, in the further analyzed immune response pathway we note a strong upregulation of thrombospondin 1 (THBS1) and integrin β1 (ITGB1) in response to CT as well as to mmCT and dmLT, mediated via cAMP/PKA and NFKB signaling. Importantly, inhibition
in vitro
of THSB1 and ITGB1 in monocytes or primary dendritic cells using siRNA abrogated the ability of the treated APCs to promote an adjuvant-stimulated Th17 cell response when co-cultured with peripheral blood lymphocytes indicating the involvement of these molecules in the adjuvant action on APCs by CT, mmCT and dmLT.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30808871</pmid><doi>10.1038/s41598-019-38726-0</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-8799-7645</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 101/47 13/31 38/89 631/250/590 631/80/86 82/80 Adjuvants Antigen-presenting cells Cholera Cholera toxin Cyclic AMP Dendritic cells Helper cells Humanities and Social Sciences IL-1β Immune response Inflammasomes Kinases Lymphocytes Lymphocytes T Monocytes multidisciplinary NF-κB protein Peripheral blood Protein kinase A Science Science (multidisciplinary) Signal transduction siRNA Thrombospondin Toxins Waterborne diseases |
| title | Proteomic analysis of cholera toxin adjuvant-stimulated human monocytes identifies Thrombospondin-1 and Integrin-β1 as strongly upregulated molecules involved in adjuvant activity |
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