Soluble interleukin-15 complexes are generated in vivo by type I interferon dependent and independent pathways
Interleukin (IL)-15 associates with IL-15Rα on the cell surface where it can be cleaved into soluble cytokine/receptor complexes that have the potential to stimulate CD8 T cells and NK cells. Unfortunately, little is known about the in vivo production of soluble IL-15Rα/IL-15 complexes (sIL-15 compl...
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| description | Interleukin (IL)-15 associates with IL-15Rα on the cell surface where it can be cleaved into soluble cytokine/receptor complexes that have the potential to stimulate CD8 T cells and NK cells. Unfortunately, little is known about the in vivo production of soluble IL-15Rα/IL-15 complexes (sIL-15 complexes), particularly regarding the circumstances that induce them and the mechanisms responsible. The main objective of this study was to elucidate the signals leading to the generation of sIL-15 complexes. In this study, we show that sIL-15 complexes are increased in the serum of mice in response to Interferon (IFN)-α. In bone marrow derived dendritic cells (BMDC), IFN-α increased the activity of ADAM17, a metalloproteinase implicated in cleaving IL-15 complexes from the cell surface. Moreover, knocking out ADAM17 in BMDCs prevented the ability of IFN-α to induce sIL-15 complexes demonstrating ADAM17 as a critical protease mediating cleavage of IL-15 complexes in response to type I IFNs. Type I IFN signaling was required for generating sIL-15 complexes as in vivo induction of sIL-15 complexes by Poly I:C stimulation or total body irradiation (TBI) was impaired in IFNAR-/- mice. Interestingly, serum sIL-15 complexes were also induced in mice infected with Vesicular stomatitis virus (VSV) or mice treated with agonistic CD40 antibodies; however, sIL-15 complexes were still induced in IFNAR-/- mice after VSV infection or CD40 stimulation indicating pathways other than type I IFNs induce sIL-15 complexes. Overall, this study has shown that type I IFNs, VSV infection, and CD40 stimulation induce sIL-15 complexes suggesting the generation of sIL-15 complexes is a common event associated with immune activation. These findings reveal an unrealized mechanism for enhanced immune responses occurring during infection, vaccination, inflammation, and autoimmunity. |
| doi_str_mv | 10.1371/journal.pone.0120274 |
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Unfortunately, little is known about the in vivo production of soluble IL-15Rα/IL-15 complexes (sIL-15 complexes), particularly regarding the circumstances that induce them and the mechanisms responsible. The main objective of this study was to elucidate the signals leading to the generation of sIL-15 complexes. In this study, we show that sIL-15 complexes are increased in the serum of mice in response to Interferon (IFN)-α. In bone marrow derived dendritic cells (BMDC), IFN-α increased the activity of ADAM17, a metalloproteinase implicated in cleaving IL-15 complexes from the cell surface. Moreover, knocking out ADAM17 in BMDCs prevented the ability of IFN-α to induce sIL-15 complexes demonstrating ADAM17 as a critical protease mediating cleavage of IL-15 complexes in response to type I IFNs. Type I IFN signaling was required for generating sIL-15 complexes as in vivo induction of sIL-15 complexes by Poly I:C stimulation or total body irradiation (TBI) was impaired in IFNAR-/- mice. Interestingly, serum sIL-15 complexes were also induced in mice infected with Vesicular stomatitis virus (VSV) or mice treated with agonistic CD40 antibodies; however, sIL-15 complexes were still induced in IFNAR-/- mice after VSV infection or CD40 stimulation indicating pathways other than type I IFNs induce sIL-15 complexes. Overall, this study has shown that type I IFNs, VSV infection, and CD40 stimulation induce sIL-15 complexes suggesting the generation of sIL-15 complexes is a common event associated with immune activation. These findings reveal an unrealized mechanism for enhanced immune responses occurring during infection, vaccination, inflammation, and autoimmunity.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0120274</identifier><identifier>PMID: 25756182</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Antibodies ; Autoimmunity ; Biological response modifiers ; Bone marrow ; Cancer ; CD40 antigen ; CD40 Antigens - metabolism ; CD8 antigen ; Cell surface ; Cells, Cultured ; Cytokines ; Dendritic cells ; Dendritic Cells - metabolism ; Departments ; Homeostasis ; Immune response ; Immunology ; Infections ; Interferon ; Interferon-alpha - physiology ; Interleukin 15 ; Interleukin-15 - blood ; Irradiation ; Killer cells ; Laboratory animals ; Lymphocytes ; Lymphocytes T ; Melanoma ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Physiological aspects ; Polyinosinic:polycytidylic acid ; Psoriasis ; Radiation ; Receptor, Interferon alpha-beta - metabolism ; Signaling ; Stimulation ; Stomatitis ; Studies ; Vaccination ; Vesicular Stomatitis - blood ; Viruses ; Whole-Body Irradiation</subject><ispartof>PloS one, 2015-03, Vol.10 (3), p.e0120274-e0120274</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Anthony et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Anthony et al 2015 Anthony et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c585t-5c46b9f459fbdbedd3e7f6c904c766d7e9a66a7425616027f6c61ed910a83ce53</citedby><cites>FETCH-LOGICAL-c585t-5c46b9f459fbdbedd3e7f6c904c766d7e9a66a7425616027f6c61ed910a83ce53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354909/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354909/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25756182$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Anthony, Scott M</creatorcontrib><creatorcontrib>Howard, Megan E</creatorcontrib><creatorcontrib>Hailemichael, Yared</creatorcontrib><creatorcontrib>Overwijk, Willem W</creatorcontrib><creatorcontrib>Schluns, Kimberly S</creatorcontrib><title>Soluble interleukin-15 complexes are generated in vivo by type I interferon dependent and independent pathways</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Interleukin (IL)-15 associates with IL-15Rα on the cell surface where it can be cleaved into soluble cytokine/receptor complexes that have the potential to stimulate CD8 T cells and NK cells. Unfortunately, little is known about the in vivo production of soluble IL-15Rα/IL-15 complexes (sIL-15 complexes), particularly regarding the circumstances that induce them and the mechanisms responsible. The main objective of this study was to elucidate the signals leading to the generation of sIL-15 complexes. In this study, we show that sIL-15 complexes are increased in the serum of mice in response to Interferon (IFN)-α. In bone marrow derived dendritic cells (BMDC), IFN-α increased the activity of ADAM17, a metalloproteinase implicated in cleaving IL-15 complexes from the cell surface. Moreover, knocking out ADAM17 in BMDCs prevented the ability of IFN-α to induce sIL-15 complexes demonstrating ADAM17 as a critical protease mediating cleavage of IL-15 complexes in response to type I IFNs. Type I IFN signaling was required for generating sIL-15 complexes as in vivo induction of sIL-15 complexes by Poly I:C stimulation or total body irradiation (TBI) was impaired in IFNAR-/- mice. Interestingly, serum sIL-15 complexes were also induced in mice infected with Vesicular stomatitis virus (VSV) or mice treated with agonistic CD40 antibodies; however, sIL-15 complexes were still induced in IFNAR-/- mice after VSV infection or CD40 stimulation indicating pathways other than type I IFNs induce sIL-15 complexes. Overall, this study has shown that type I IFNs, VSV infection, and CD40 stimulation induce sIL-15 complexes suggesting the generation of sIL-15 complexes is a common event associated with immune activation. These findings reveal an unrealized mechanism for enhanced immune responses occurring during infection, vaccination, inflammation, and autoimmunity.</description><subject>Animals</subject><subject>Antibodies</subject><subject>Autoimmunity</subject><subject>Biological response modifiers</subject><subject>Bone marrow</subject><subject>Cancer</subject><subject>CD40 antigen</subject><subject>CD40 Antigens - metabolism</subject><subject>CD8 antigen</subject><subject>Cell surface</subject><subject>Cells, Cultured</subject><subject>Cytokines</subject><subject>Dendritic cells</subject><subject>Dendritic Cells - metabolism</subject><subject>Departments</subject><subject>Homeostasis</subject><subject>Immune response</subject><subject>Immunology</subject><subject>Infections</subject><subject>Interferon</subject><subject>Interferon-alpha - physiology</subject><subject>Interleukin 15</subject><subject>Interleukin-15 - blood</subject><subject>Irradiation</subject><subject>Killer cells</subject><subject>Laboratory animals</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Melanoma</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Physiological aspects</subject><subject>Polyinosinic:polycytidylic acid</subject><subject>Psoriasis</subject><subject>Radiation</subject><subject>Receptor, Interferon alpha-beta - metabolism</subject><subject>Signaling</subject><subject>Stimulation</subject><subject>Stomatitis</subject><subject>Studies</subject><subject>Vaccination</subject><subject>Vesicular Stomatitis - blood</subject><subject>Viruses</subject><subject>Whole-Body Irradiation</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptkktv1DAUhSMEoqXwDxBEQkJspvideFOpqniMVIkFsLYc-2Ymg8cOdjIw_x6nk5YZxMqv7557j3WK4iVGl5hW-P0mjNFrd9kHD5cIE0Qq9qg4x5KShSCIPj7anxXPUtogxGktxNPijPCKC1yT88J_DW5sHJSdHyA6GH90foF5acK2d_AbUqkjlCvwEPUANmPlrtuFstmXw76HcnkobCEGX1rowVvwQ6n9hP4993pY_9L79Lx40mqX4MW8XhTfP374dvN5cfvl0_Lm-nZheM2HBTdMNLJlXLaNbcBaClUrjETMVELYCqQWQleMZBciG89vAoOVGOmaGuD0onh90O1dSGr-qqSwEFjWlcATsTwQNuiN6mO31XGvgu7U3UWIK6Xj0BkHKk-ggWDBeE0YIkQiI0xtJcVQi4pUWetq7jY2W7AmO47anYievvhurVZhpxjlTCKZBd7NAjH8HCENatslA85pD2G8m5sIyjmf0Df_oP93N1MrnQ10vg25r5lE1TUjgue5JcrU2yNqDdoN65TzMHTBp1OQHUATQ0oR2gdvGKkpjfdDqCmNak5jLnt1_C8PRffxo38AqPrc2Q</recordid><startdate>20150310</startdate><enddate>20150310</enddate><creator>Anthony, Scott M</creator><creator>Howard, Megan E</creator><creator>Hailemichael, Yared</creator><creator>Overwijk, Willem W</creator><creator>Schluns, Kimberly S</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150310</creationdate><title>Soluble interleukin-15 complexes are generated in vivo by type I interferon dependent and independent pathways</title><author>Anthony, Scott M ; Howard, Megan E ; Hailemichael, Yared ; Overwijk, Willem W ; Schluns, Kimberly S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c585t-5c46b9f459fbdbedd3e7f6c904c766d7e9a66a7425616027f6c61ed910a83ce53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Antibodies</topic><topic>Autoimmunity</topic><topic>Biological response modifiers</topic><topic>Bone marrow</topic><topic>Cancer</topic><topic>CD40 antigen</topic><topic>CD40 Antigens - metabolism</topic><topic>CD8 antigen</topic><topic>Cell surface</topic><topic>Cells, Cultured</topic><topic>Cytokines</topic><topic>Dendritic cells</topic><topic>Dendritic Cells - metabolism</topic><topic>Departments</topic><topic>Homeostasis</topic><topic>Immune response</topic><topic>Immunology</topic><topic>Infections</topic><topic>Interferon</topic><topic>Interferon-alpha - physiology</topic><topic>Interleukin 15</topic><topic>Interleukin-15 - blood</topic><topic>Irradiation</topic><topic>Killer cells</topic><topic>Laboratory animals</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Melanoma</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Physiological aspects</topic><topic>Polyinosinic:polycytidylic acid</topic><topic>Psoriasis</topic><topic>Radiation</topic><topic>Receptor, Interferon alpha-beta - metabolism</topic><topic>Signaling</topic><topic>Stimulation</topic><topic>Stomatitis</topic><topic>Studies</topic><topic>Vaccination</topic><topic>Vesicular Stomatitis - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Anthony, Scott M</au><au>Howard, Megan E</au><au>Hailemichael, Yared</au><au>Overwijk, Willem W</au><au>Schluns, Kimberly S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Soluble interleukin-15 complexes are generated in vivo by type I interferon dependent and independent pathways</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-03-10</date><risdate>2015</risdate><volume>10</volume><issue>3</issue><spage>e0120274</spage><epage>e0120274</epage><pages>e0120274-e0120274</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Interleukin (IL)-15 associates with IL-15Rα on the cell surface where it can be cleaved into soluble cytokine/receptor complexes that have the potential to stimulate CD8 T cells and NK cells. Unfortunately, little is known about the in vivo production of soluble IL-15Rα/IL-15 complexes (sIL-15 complexes), particularly regarding the circumstances that induce them and the mechanisms responsible. The main objective of this study was to elucidate the signals leading to the generation of sIL-15 complexes. In this study, we show that sIL-15 complexes are increased in the serum of mice in response to Interferon (IFN)-α. In bone marrow derived dendritic cells (BMDC), IFN-α increased the activity of ADAM17, a metalloproteinase implicated in cleaving IL-15 complexes from the cell surface. Moreover, knocking out ADAM17 in BMDCs prevented the ability of IFN-α to induce sIL-15 complexes demonstrating ADAM17 as a critical protease mediating cleavage of IL-15 complexes in response to type I IFNs. Type I IFN signaling was required for generating sIL-15 complexes as in vivo induction of sIL-15 complexes by Poly I:C stimulation or total body irradiation (TBI) was impaired in IFNAR-/- mice. Interestingly, serum sIL-15 complexes were also induced in mice infected with Vesicular stomatitis virus (VSV) or mice treated with agonistic CD40 antibodies; however, sIL-15 complexes were still induced in IFNAR-/- mice after VSV infection or CD40 stimulation indicating pathways other than type I IFNs induce sIL-15 complexes. Overall, this study has shown that type I IFNs, VSV infection, and CD40 stimulation induce sIL-15 complexes suggesting the generation of sIL-15 complexes is a common event associated with immune activation. These findings reveal an unrealized mechanism for enhanced immune responses occurring during infection, vaccination, inflammation, and autoimmunity.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25756182</pmid><doi>10.1371/journal.pone.0120274</doi><oa>free_for_read</oa></addata></record> |
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| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Antibodies Autoimmunity Biological response modifiers Bone marrow Cancer CD40 antigen CD40 Antigens - metabolism CD8 antigen Cell surface Cells, Cultured Cytokines Dendritic cells Dendritic Cells - metabolism Departments Homeostasis Immune response Immunology Infections Interferon Interferon-alpha - physiology Interleukin 15 Interleukin-15 - blood Irradiation Killer cells Laboratory animals Lymphocytes Lymphocytes T Melanoma Mice Mice, Inbred C57BL Mice, Knockout Physiological aspects Polyinosinic:polycytidylic acid Psoriasis Radiation Receptor, Interferon alpha-beta - metabolism Signaling Stimulation Stomatitis Studies Vaccination Vesicular Stomatitis - blood Viruses Whole-Body Irradiation |
| title | Soluble interleukin-15 complexes are generated in vivo by type I interferon dependent and independent pathways |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-21T22%3A24%3A48IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Soluble%20interleukin-15%20complexes%20are%20generated%20in%20vivo%20by%20type%20I%20interferon%20dependent%20and%20independent%20pathways&rft.jtitle=PloS%20one&rft.au=Anthony,%20Scott%20M&rft.date=2015-03-10&rft.volume=10&rft.issue=3&rft.spage=e0120274&rft.epage=e0120274&rft.pages=e0120274-e0120274&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0120274&rft_dat=%3Cgale_plos_%3EA426586790%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1661987615&rft_id=info:pmid/25756182&rft_galeid=A426586790&rft_doaj_id=oai_doaj_org_article_dbeae2164582402290c6c8d931e86727&rfr_iscdi=true |