Mesenchymal stem cells attenuate acute liver injury by altering ratio between interleukin 17 producing and regulatory natural killer T cells
Mesenchymal stem cells (MSCs) are, due to immunomodulatory characteristics, considered as novel agents in the treatment of immune‐mediated acute liver failure. Although it is known that MSCs can regulate activation of T lymphocytes, their capacity to modulate function of neutrophils and natural kill...
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| Veröffentlicht in: | Liver transplantation 2017-08, Vol.23 (8), p.1040-1050 |
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| creator | Milosavljevic, Neda Gazdic, Marina Simovic Markovic, Bojana Arsenijevic, Aleksandar Nurkovic, Jasmin Dolicanin, Zana Djonov, Valentin Lukic, Miodrag L. Volarevic, Vladislav |
| description | Mesenchymal stem cells (MSCs) are, due to immunomodulatory characteristics, considered as novel agents in the treatment of immune‐mediated acute liver failure. Although it is known that MSCs can regulate activation of T lymphocytes, their capacity to modulate function of neutrophils and natural killer T (NKT) cells, major interleukin (IL) 17–producing cells in acute liver injury, is still unknown. By using 2 well‐established murine models of neutrophil and NKT cell–mediated acute liver failure (induced by carbon tetrachloride and α‐galactoceramide), we investigated molecular and cellular mechanisms involved in MSC‐mediated modulation of IL17 signaling during acute liver injury. Single intravenous injection of MSCs attenuate acute hepatitis and hepatotoxicity of NKT cells in a paracrine, indoleamine 2,3‐dioxygenase (IDO)–dependent manner. Decreased levels of inflammatory IL17 and increased levels of immunosuppressive IL10 in serum, reduced number of interleukin 17–producing natural killer T (NKT17) cells, and increased presence of forkhead box P3 + IL10–producing natural killer T regulatory cells (NKTregs) were noticed in the injured livers of MSC‐treated mice. MSCs did not significantly alter the total number of IL17‐producing neutrophils, CD4+, and CD8 + T lymphocytes in the injured livers. Injection of mesenchymal stem cell–conditioned medium (MSC‐CM) resulted with an increased NKTreg/NKT17 ratio in the liver and attenuated hepatitis in vivo and significantly reduced hepatotoxicity of NKT cells in vitro. This phenomenon was completely abrogated in the presence of IDO inhibitor, 1‐methyltryptophan. In conclusion, the capacity of MSCs to alter NKT17/NKTreg ratio and suppress hepatotoxicity of NKT cells in an IDO‐dependent manner may be used as a new therapeutic approach in IL17‐driven liver inflammation. Liver Transplantation 23 1040–1050 2017 AASLD. |
| doi_str_mv | 10.1002/lt.24784 |
| format | Article |
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Although it is known that MSCs can regulate activation of T lymphocytes, their capacity to modulate function of neutrophils and natural killer T (NKT) cells, major interleukin (IL) 17–producing cells in acute liver injury, is still unknown. By using 2 well‐established murine models of neutrophil and NKT cell–mediated acute liver failure (induced by carbon tetrachloride and α‐galactoceramide), we investigated molecular and cellular mechanisms involved in MSC‐mediated modulation of IL17 signaling during acute liver injury. Single intravenous injection of MSCs attenuate acute hepatitis and hepatotoxicity of NKT cells in a paracrine, indoleamine 2,3‐dioxygenase (IDO)–dependent manner. Decreased levels of inflammatory IL17 and increased levels of immunosuppressive IL10 in serum, reduced number of interleukin 17–producing natural killer T (NKT17) cells, and increased presence of forkhead box P3 + IL10–producing natural killer T regulatory cells (NKTregs) were noticed in the injured livers of MSC‐treated mice. MSCs did not significantly alter the total number of IL17‐producing neutrophils, CD4+, and CD8 + T lymphocytes in the injured livers. Injection of mesenchymal stem cell–conditioned medium (MSC‐CM) resulted with an increased NKTreg/NKT17 ratio in the liver and attenuated hepatitis in vivo and significantly reduced hepatotoxicity of NKT cells in vitro. This phenomenon was completely abrogated in the presence of IDO inhibitor, 1‐methyltryptophan. In conclusion, the capacity of MSCs to alter NKT17/NKTreg ratio and suppress hepatotoxicity of NKT cells in an IDO‐dependent manner may be used as a new therapeutic approach in IL17‐driven liver inflammation. Liver Transplantation 23 1040–1050 2017 AASLD.</description><identifier>ISSN: 1527-6465</identifier><identifier>EISSN: 1527-6473</identifier><identifier>DOI: 10.1002/lt.24784</identifier><identifier>PMID: 28481005</identifier><language>eng</language><publisher>United States: Wolters Kluwer Health, Inc</publisher><subject>Animal models ; Animals ; Carbon tetrachloride ; Carbon Tetrachloride - pharmacology ; CD4 antigen ; CD8 antigen ; CD8-Positive T-Lymphocytes - immunology ; CD8-Positive T-Lymphocytes - metabolism ; Cell activation ; Cells, Cultured ; Coculture Techniques ; Cytokines ; Disease Models, Animal ; Forkhead protein ; Forkhead Transcription Factors - metabolism ; Galactosylceramides - pharmacology ; Hepatitis ; Hepatocytes ; Hepatotoxicity ; Humans ; Immunomodulation ; Immunoregulation ; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors ; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism ; Inflammation ; Injection ; Interleukin 1 ; Interleukin 10 ; Interleukin 17 ; Interleukin-17 - metabolism ; Intravenous administration ; Leukocytes (neutrophilic) ; Liver ; Liver diseases ; Liver Failure, Acute - immunology ; Liver Failure, Acute - therapy ; Lymphocytes T ; Male ; Mesenchymal Stem Cell Transplantation ; Mesenchymal stem cells ; Mesenchymal Stem Cells - immunology ; Mesenchyme ; Mice ; Mice, Inbred C57BL ; Natural Killer T-Cells - drug effects ; Natural Killer T-Cells - immunology ; Natural Killer T-Cells - metabolism ; Neutrophils ; Neutrophils - immunology ; Neutrophils - metabolism ; Rodents ; Stem cells ; T cell receptors ; T-Lymphocytes, Regulatory - immunology ; T-Lymphocytes, Regulatory - metabolism ; Th17 Cells - immunology ; Th17 Cells - metabolism ; Tryptophan - analogs & derivatives ; Tryptophan - pharmacology ; Tryptophan 2,3-dioxygenase</subject><ispartof>Liver transplantation, 2017-08, Vol.23 (8), p.1040-1050</ispartof><rights>2017 by the American Association for the Study of Liver Diseases.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3834-8fa50b7218c1aeddb1e0a893aa55d6a594c5ae2ace5b5a123be773fe135fb8813</citedby><cites>FETCH-LOGICAL-c3834-8fa50b7218c1aeddb1e0a893aa55d6a594c5ae2ace5b5a123be773fe135fb8813</cites><orcidid>0000-0001-6369-6285</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Flt.24784$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Flt.24784$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28481005$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Milosavljevic, Neda</creatorcontrib><creatorcontrib>Gazdic, Marina</creatorcontrib><creatorcontrib>Simovic Markovic, Bojana</creatorcontrib><creatorcontrib>Arsenijevic, Aleksandar</creatorcontrib><creatorcontrib>Nurkovic, Jasmin</creatorcontrib><creatorcontrib>Dolicanin, Zana</creatorcontrib><creatorcontrib>Djonov, Valentin</creatorcontrib><creatorcontrib>Lukic, Miodrag L.</creatorcontrib><creatorcontrib>Volarevic, Vladislav</creatorcontrib><title>Mesenchymal stem cells attenuate acute liver injury by altering ratio between interleukin 17 producing and regulatory natural killer T cells</title><title>Liver transplantation</title><addtitle>Liver Transpl</addtitle><description>Mesenchymal stem cells (MSCs) are, due to immunomodulatory characteristics, considered as novel agents in the treatment of immune‐mediated acute liver failure. Although it is known that MSCs can regulate activation of T lymphocytes, their capacity to modulate function of neutrophils and natural killer T (NKT) cells, major interleukin (IL) 17–producing cells in acute liver injury, is still unknown. By using 2 well‐established murine models of neutrophil and NKT cell–mediated acute liver failure (induced by carbon tetrachloride and α‐galactoceramide), we investigated molecular and cellular mechanisms involved in MSC‐mediated modulation of IL17 signaling during acute liver injury. Single intravenous injection of MSCs attenuate acute hepatitis and hepatotoxicity of NKT cells in a paracrine, indoleamine 2,3‐dioxygenase (IDO)–dependent manner. Decreased levels of inflammatory IL17 and increased levels of immunosuppressive IL10 in serum, reduced number of interleukin 17–producing natural killer T (NKT17) cells, and increased presence of forkhead box P3 + IL10–producing natural killer T regulatory cells (NKTregs) were noticed in the injured livers of MSC‐treated mice. MSCs did not significantly alter the total number of IL17‐producing neutrophils, CD4+, and CD8 + T lymphocytes in the injured livers. Injection of mesenchymal stem cell–conditioned medium (MSC‐CM) resulted with an increased NKTreg/NKT17 ratio in the liver and attenuated hepatitis in vivo and significantly reduced hepatotoxicity of NKT cells in vitro. This phenomenon was completely abrogated in the presence of IDO inhibitor, 1‐methyltryptophan. In conclusion, the capacity of MSCs to alter NKT17/NKTreg ratio and suppress hepatotoxicity of NKT cells in an IDO‐dependent manner may be used as a new therapeutic approach in IL17‐driven liver inflammation. Liver Transplantation 23 1040–1050 2017 AASLD.</description><subject>Animal models</subject><subject>Animals</subject><subject>Carbon tetrachloride</subject><subject>Carbon Tetrachloride - pharmacology</subject><subject>CD4 antigen</subject><subject>CD8 antigen</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>CD8-Positive T-Lymphocytes - metabolism</subject><subject>Cell activation</subject><subject>Cells, Cultured</subject><subject>Coculture Techniques</subject><subject>Cytokines</subject><subject>Disease Models, Animal</subject><subject>Forkhead protein</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Galactosylceramides - pharmacology</subject><subject>Hepatitis</subject><subject>Hepatocytes</subject><subject>Hepatotoxicity</subject><subject>Humans</subject><subject>Immunomodulation</subject><subject>Immunoregulation</subject><subject>Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors</subject><subject>Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism</subject><subject>Inflammation</subject><subject>Injection</subject><subject>Interleukin 1</subject><subject>Interleukin 10</subject><subject>Interleukin 17</subject><subject>Interleukin-17 - metabolism</subject><subject>Intravenous administration</subject><subject>Leukocytes (neutrophilic)</subject><subject>Liver</subject><subject>Liver diseases</subject><subject>Liver Failure, Acute - immunology</subject><subject>Liver Failure, Acute - therapy</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Mesenchymal Stem Cell Transplantation</subject><subject>Mesenchymal stem cells</subject><subject>Mesenchymal Stem Cells - immunology</subject><subject>Mesenchyme</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Natural Killer T-Cells - drug effects</subject><subject>Natural Killer T-Cells - immunology</subject><subject>Natural Killer T-Cells - metabolism</subject><subject>Neutrophils</subject><subject>Neutrophils - immunology</subject><subject>Neutrophils - metabolism</subject><subject>Rodents</subject><subject>Stem cells</subject><subject>T cell receptors</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>T-Lymphocytes, Regulatory - metabolism</subject><subject>Th17 Cells - immunology</subject><subject>Th17 Cells - metabolism</subject><subject>Tryptophan - analogs & derivatives</subject><subject>Tryptophan - pharmacology</subject><subject>Tryptophan 2,3-dioxygenase</subject><issn>1527-6465</issn><issn>1527-6473</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMtKxDAUhoMo3sEnkIAbN9UkbaaZpYg3GHEzrstpejp2zKSai0PfwYc2Y9WdmySE73z_4SfkhLMLzpi4NOFCFKUqtsg-l6LMJkWZb_-9J3KPHHi_ZIxzOWW7ZE-oQqVBuU8-H9Gj1S_DCgz1AVdUozGeQghoIwSkoGM6TfeBjnZ2Gd1A64GCCeg6u6AOQtfTGsMa0SYgfRuMr52lvKRvrm-i3mBgG-pwEQ2EPhkshOhS4mtnTPLOx9QjstOC8Xj8cx-S59ub-fV9Nnu6e7i-mmU6V3mRqRYkq0vBleaATVNzZKCmOYCUzQTktNASUIBGWUvgIq-xLPMWeS7bWimeH5Kz0Zv2e4_oQ7Xso7MpsuJTwVjJBVOJOh8p7XrvHbbVm-tW4IaKs2pTe2VC9V17Qk9_hLFeYfMH_vacgGwE1p3B4V9RNZuPwi8UN45Q</recordid><startdate>201708</startdate><enddate>201708</enddate><creator>Milosavljevic, Neda</creator><creator>Gazdic, Marina</creator><creator>Simovic Markovic, Bojana</creator><creator>Arsenijevic, Aleksandar</creator><creator>Nurkovic, Jasmin</creator><creator>Dolicanin, Zana</creator><creator>Djonov, Valentin</creator><creator>Lukic, Miodrag L.</creator><creator>Volarevic, Vladislav</creator><general>Wolters Kluwer Health, Inc</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>K9.</scope><orcidid>https://orcid.org/0000-0001-6369-6285</orcidid></search><sort><creationdate>201708</creationdate><title>Mesenchymal stem cells attenuate acute liver injury by altering ratio between interleukin 17 producing and regulatory natural killer T cells</title><author>Milosavljevic, Neda ; Gazdic, Marina ; Simovic Markovic, Bojana ; Arsenijevic, Aleksandar ; Nurkovic, Jasmin ; Dolicanin, Zana ; Djonov, Valentin ; Lukic, Miodrag L. ; Volarevic, Vladislav</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3834-8fa50b7218c1aeddb1e0a893aa55d6a594c5ae2ace5b5a123be773fe135fb8813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Carbon tetrachloride</topic><topic>Carbon Tetrachloride - pharmacology</topic><topic>CD4 antigen</topic><topic>CD8 antigen</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>CD8-Positive T-Lymphocytes - metabolism</topic><topic>Cell activation</topic><topic>Cells, Cultured</topic><topic>Coculture Techniques</topic><topic>Cytokines</topic><topic>Disease Models, Animal</topic><topic>Forkhead protein</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Galactosylceramides - pharmacology</topic><topic>Hepatitis</topic><topic>Hepatocytes</topic><topic>Hepatotoxicity</topic><topic>Humans</topic><topic>Immunomodulation</topic><topic>Immunoregulation</topic><topic>Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors</topic><topic>Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism</topic><topic>Inflammation</topic><topic>Injection</topic><topic>Interleukin 1</topic><topic>Interleukin 10</topic><topic>Interleukin 17</topic><topic>Interleukin-17 - metabolism</topic><topic>Intravenous administration</topic><topic>Leukocytes (neutrophilic)</topic><topic>Liver</topic><topic>Liver diseases</topic><topic>Liver Failure, Acute - immunology</topic><topic>Liver Failure, Acute - therapy</topic><topic>Lymphocytes T</topic><topic>Male</topic><topic>Mesenchymal Stem Cell Transplantation</topic><topic>Mesenchymal stem cells</topic><topic>Mesenchymal Stem Cells - immunology</topic><topic>Mesenchyme</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Natural Killer T-Cells - drug effects</topic><topic>Natural Killer T-Cells - immunology</topic><topic>Natural Killer T-Cells - metabolism</topic><topic>Neutrophils</topic><topic>Neutrophils - immunology</topic><topic>Neutrophils - metabolism</topic><topic>Rodents</topic><topic>Stem cells</topic><topic>T cell receptors</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>T-Lymphocytes, Regulatory - metabolism</topic><topic>Th17 Cells - immunology</topic><topic>Th17 Cells - metabolism</topic><topic>Tryptophan - analogs & derivatives</topic><topic>Tryptophan - pharmacology</topic><topic>Tryptophan 2,3-dioxygenase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Milosavljevic, Neda</creatorcontrib><creatorcontrib>Gazdic, Marina</creatorcontrib><creatorcontrib>Simovic Markovic, Bojana</creatorcontrib><creatorcontrib>Arsenijevic, Aleksandar</creatorcontrib><creatorcontrib>Nurkovic, Jasmin</creatorcontrib><creatorcontrib>Dolicanin, Zana</creatorcontrib><creatorcontrib>Djonov, Valentin</creatorcontrib><creatorcontrib>Lukic, Miodrag L.</creatorcontrib><creatorcontrib>Volarevic, Vladislav</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><jtitle>Liver transplantation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Milosavljevic, Neda</au><au>Gazdic, Marina</au><au>Simovic Markovic, Bojana</au><au>Arsenijevic, Aleksandar</au><au>Nurkovic, Jasmin</au><au>Dolicanin, Zana</au><au>Djonov, Valentin</au><au>Lukic, Miodrag L.</au><au>Volarevic, Vladislav</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mesenchymal stem cells attenuate acute liver injury by altering ratio between interleukin 17 producing and regulatory natural killer T cells</atitle><jtitle>Liver transplantation</jtitle><addtitle>Liver Transpl</addtitle><date>2017-08</date><risdate>2017</risdate><volume>23</volume><issue>8</issue><spage>1040</spage><epage>1050</epage><pages>1040-1050</pages><issn>1527-6465</issn><eissn>1527-6473</eissn><abstract>Mesenchymal stem cells (MSCs) are, due to immunomodulatory characteristics, considered as novel agents in the treatment of immune‐mediated acute liver failure. Although it is known that MSCs can regulate activation of T lymphocytes, their capacity to modulate function of neutrophils and natural killer T (NKT) cells, major interleukin (IL) 17–producing cells in acute liver injury, is still unknown. By using 2 well‐established murine models of neutrophil and NKT cell–mediated acute liver failure (induced by carbon tetrachloride and α‐galactoceramide), we investigated molecular and cellular mechanisms involved in MSC‐mediated modulation of IL17 signaling during acute liver injury. Single intravenous injection of MSCs attenuate acute hepatitis and hepatotoxicity of NKT cells in a paracrine, indoleamine 2,3‐dioxygenase (IDO)–dependent manner. Decreased levels of inflammatory IL17 and increased levels of immunosuppressive IL10 in serum, reduced number of interleukin 17–producing natural killer T (NKT17) cells, and increased presence of forkhead box P3 + IL10–producing natural killer T regulatory cells (NKTregs) were noticed in the injured livers of MSC‐treated mice. MSCs did not significantly alter the total number of IL17‐producing neutrophils, CD4+, and CD8 + T lymphocytes in the injured livers. Injection of mesenchymal stem cell–conditioned medium (MSC‐CM) resulted with an increased NKTreg/NKT17 ratio in the liver and attenuated hepatitis in vivo and significantly reduced hepatotoxicity of NKT cells in vitro. This phenomenon was completely abrogated in the presence of IDO inhibitor, 1‐methyltryptophan. In conclusion, the capacity of MSCs to alter NKT17/NKTreg ratio and suppress hepatotoxicity of NKT cells in an IDO‐dependent manner may be used as a new therapeutic approach in IL17‐driven liver inflammation. Liver Transplantation 23 1040–1050 2017 AASLD.</abstract><cop>United States</cop><pub>Wolters Kluwer Health, Inc</pub><pmid>28481005</pmid><doi>10.1002/lt.24784</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-6369-6285</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Liver transplantation, 2017-08, Vol.23 (8), p.1040-1050 |
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| language | eng |
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| source | MEDLINE; Wiley Online Library; Alma/SFX Local Collection |
| subjects | Animal models Animals Carbon tetrachloride Carbon Tetrachloride - pharmacology CD4 antigen CD8 antigen CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cell activation Cells, Cultured Coculture Techniques Cytokines Disease Models, Animal Forkhead protein Forkhead Transcription Factors - metabolism Galactosylceramides - pharmacology Hepatitis Hepatocytes Hepatotoxicity Humans Immunomodulation Immunoregulation Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism Inflammation Injection Interleukin 1 Interleukin 10 Interleukin 17 Interleukin-17 - metabolism Intravenous administration Leukocytes (neutrophilic) Liver Liver diseases Liver Failure, Acute - immunology Liver Failure, Acute - therapy Lymphocytes T Male Mesenchymal Stem Cell Transplantation Mesenchymal stem cells Mesenchymal Stem Cells - immunology Mesenchyme Mice Mice, Inbred C57BL Natural Killer T-Cells - drug effects Natural Killer T-Cells - immunology Natural Killer T-Cells - metabolism Neutrophils Neutrophils - immunology Neutrophils - metabolism Rodents Stem cells T cell receptors T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - metabolism Th17 Cells - immunology Th17 Cells - metabolism Tryptophan - analogs & derivatives Tryptophan - pharmacology Tryptophan 2,3-dioxygenase |
| title | Mesenchymal stem cells attenuate acute liver injury by altering ratio between interleukin 17 producing and regulatory natural killer T cells |
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