IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO
Context: The development of thyroid-associated ophthalmopathy (TAO) is associated with self-immune dysfunction. Recent findings in TAO and Graves' disease indicate that IL-17A may also be involved in the autoimmunity of TAO. Objective: We sought to investigate the pathogenic function of IL-17A-...
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| Veröffentlicht in: | The journal of clinical endocrinology and metabolism 2016-08, Vol.101 (8), p.2955-2965 |
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| creator | Fang, Sijie Huang, Yazhuo Wang, Shuaiwei Zhang, Yidan Luo, Xuerui Liu, Luyan Zhong, Sisi Liu, Xingtong Li, Dan Liang, Rui Miranda, Piccioni Gu, Ping Zhou, Huifang Fan, Xianqun Li, Bin |
| description | Context:
The development of thyroid-associated ophthalmopathy (TAO) is associated with self-immune dysfunction. Recent findings in TAO and Graves' disease indicate that IL-17A may also be involved in the autoimmunity of TAO.
Objective:
We sought to investigate the pathogenic function of IL-17A-producing T cells in TAO.
Design/Setting/Participants:
Blood samples and orbital fibroblasts (OFs) were collected from TAO patients and healthy subjects.
Main Outcome Measures:
Flow cytometry, real-time PCR, cytokine-specific ELISA, and Western blotting were performed.
Results:
Here, we showed a significantly higher proportion of IL-17A-producing T cells in TAO patients and the recruitment of both CD4+ and CD8+ T cells in TAO orbits. TAO orbital tissues expressed more IL-17A receptor, IL-17A, and its related cytokines, with severe fibrotic change compared with normal controls. Furthermore, we validated that IL-17A could enhance the proinflammatory function of OFs and stimulate the production of extracellular matrix proteins in OFs but not eyelid fibroblasts. The mechanisms involved in this enhancement mainly relied on MAPK activation. Finally, we observed that the deubiquitinase inhibitor vialinin A could down-regulate retinoic acid receptor-related orphan receptor-γt expression and decrease IL-17A level in TAO patients.
Conclusion:
Our observations illustrate the potential pathogenic role of IL-17A-producing T cells in the inflammatory response and fibrosis of TAO. The effect of vialinin A on the reduction of retinoic acid receptor-related orphan receptor-γt level implicates its potential role as a novel therapeutic agent for TAO and other autoimmune disorders in the future.
We reported increased IL-17A-producing T cells in TAO. IL-17A was observed to promote inflammation and fibrosis, and vialinin A could decrease IL-17A-producing T cells in TAO by destabilizing RORγt. |
| doi_str_mv | 10.1210/jc.2016-1882 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1809601656</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1809601656</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4182-290364ac426d103877d1074be63de40917af48c31e077dac38d0a399633fd6c53</originalsourceid><addsrcrecordid>eNptkM9vFCEUx4nR2LX15tlw9CAtv3Zgjpumq002WQ816Y0wDOOyzsAKTNr97wuZ6kkuLzw-75vHB4BPBF8TSvDN0VxTTBpEpKRvwIq0fI0EacVbsMKYEtQK-ngBPqR0xJhwvmbvwQUVlHLa8BVI9ztExAbePWtjY6ezTXDruhiSS7A7wx8xTCE7_wvmg60354dRT5POIZ6h9n3tDXUgOwO3szfZBQ_DAPexc1mPS1o36pQTdB4-bPZX4N2gx2Q_vtZL8HN793D7He323-5vNztkOJEU0RazhmtTFu0JZlKIUgTvbMN6y3FLhB64NIxYXJ60YbLHmrVtw9jQN2bNLsGXJfcUw5_Zpqwml4wdR-1tmJMiErdNUbduCvp1QU35eYp2UKfoJh3PimBVNaujUVWzqpoL_vk1ee4m2_-D_3otAF-ApzBmG9PvcX6yUR2sHvNB4XJ4IySqiViWG6qtmsuWMev7YKLz9hRtSuoY5uiLqv9v8wIvhpgA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1809601656</pqid></control><display><type>article</type><title>IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><source>Journals@Ovid Complete</source><creator>Fang, Sijie ; Huang, Yazhuo ; Wang, Shuaiwei ; Zhang, Yidan ; Luo, Xuerui ; Liu, Luyan ; Zhong, Sisi ; Liu, Xingtong ; Li, Dan ; Liang, Rui ; Miranda, Piccioni ; Gu, Ping ; Zhou, Huifang ; Fan, Xianqun ; Li, Bin</creator><creatorcontrib>Fang, Sijie ; Huang, Yazhuo ; Wang, Shuaiwei ; Zhang, Yidan ; Luo, Xuerui ; Liu, Luyan ; Zhong, Sisi ; Liu, Xingtong ; Li, Dan ; Liang, Rui ; Miranda, Piccioni ; Gu, Ping ; Zhou, Huifang ; Fan, Xianqun ; Li, Bin</creatorcontrib><description>Context:
The development of thyroid-associated ophthalmopathy (TAO) is associated with self-immune dysfunction. Recent findings in TAO and Graves' disease indicate that IL-17A may also be involved in the autoimmunity of TAO.
Objective:
We sought to investigate the pathogenic function of IL-17A-producing T cells in TAO.
Design/Setting/Participants:
Blood samples and orbital fibroblasts (OFs) were collected from TAO patients and healthy subjects.
Main Outcome Measures:
Flow cytometry, real-time PCR, cytokine-specific ELISA, and Western blotting were performed.
Results:
Here, we showed a significantly higher proportion of IL-17A-producing T cells in TAO patients and the recruitment of both CD4+ and CD8+ T cells in TAO orbits. TAO orbital tissues expressed more IL-17A receptor, IL-17A, and its related cytokines, with severe fibrotic change compared with normal controls. Furthermore, we validated that IL-17A could enhance the proinflammatory function of OFs and stimulate the production of extracellular matrix proteins in OFs but not eyelid fibroblasts. The mechanisms involved in this enhancement mainly relied on MAPK activation. Finally, we observed that the deubiquitinase inhibitor vialinin A could down-regulate retinoic acid receptor-related orphan receptor-γt expression and decrease IL-17A level in TAO patients.
Conclusion:
Our observations illustrate the potential pathogenic role of IL-17A-producing T cells in the inflammatory response and fibrosis of TAO. The effect of vialinin A on the reduction of retinoic acid receptor-related orphan receptor-γt level implicates its potential role as a novel therapeutic agent for TAO and other autoimmune disorders in the future.
We reported increased IL-17A-producing T cells in TAO. IL-17A was observed to promote inflammation and fibrosis, and vialinin A could decrease IL-17A-producing T cells in TAO by destabilizing RORγt.</description><identifier>ISSN: 0021-972X</identifier><identifier>EISSN: 1945-7197</identifier><identifier>DOI: 10.1210/jc.2016-1882</identifier><identifier>PMID: 27224264</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>Case-Control Studies ; Cells, Cultured ; Chemotaxis, Leukocyte - drug effects ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Fibroblasts - pathology ; Fibrosis - chemically induced ; Graves Ophthalmopathy - metabolism ; Graves Ophthalmopathy - pathology ; Humans ; Inflammation - chemically induced ; Inflammation - metabolism ; Inflammation - pathology ; Inflammation Mediators - metabolism ; Interleukin-17 - metabolism ; Interleukin-17 - pharmacology ; Orbit - metabolism ; Orbit - pathology ; T-Lymphocytes - drug effects ; T-Lymphocytes - metabolism ; Vitamin A - pharmacology</subject><ispartof>The journal of clinical endocrinology and metabolism, 2016-08, Vol.101 (8), p.2955-2965</ispartof><rights>Copyright © 2016 by the Endocrine Society</rights><rights>Copyright © 2016 by The Endocrine Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4182-290364ac426d103877d1074be63de40917af48c31e077dac38d0a399633fd6c53</citedby><cites>FETCH-LOGICAL-c4182-290364ac426d103877d1074be63de40917af48c31e077dac38d0a399633fd6c53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27224264$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fang, Sijie</creatorcontrib><creatorcontrib>Huang, Yazhuo</creatorcontrib><creatorcontrib>Wang, Shuaiwei</creatorcontrib><creatorcontrib>Zhang, Yidan</creatorcontrib><creatorcontrib>Luo, Xuerui</creatorcontrib><creatorcontrib>Liu, Luyan</creatorcontrib><creatorcontrib>Zhong, Sisi</creatorcontrib><creatorcontrib>Liu, Xingtong</creatorcontrib><creatorcontrib>Li, Dan</creatorcontrib><creatorcontrib>Liang, Rui</creatorcontrib><creatorcontrib>Miranda, Piccioni</creatorcontrib><creatorcontrib>Gu, Ping</creatorcontrib><creatorcontrib>Zhou, Huifang</creatorcontrib><creatorcontrib>Fan, Xianqun</creatorcontrib><creatorcontrib>Li, Bin</creatorcontrib><title>IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO</title><title>The journal of clinical endocrinology and metabolism</title><addtitle>J Clin Endocrinol Metab</addtitle><description>Context:
The development of thyroid-associated ophthalmopathy (TAO) is associated with self-immune dysfunction. Recent findings in TAO and Graves' disease indicate that IL-17A may also be involved in the autoimmunity of TAO.
Objective:
We sought to investigate the pathogenic function of IL-17A-producing T cells in TAO.
Design/Setting/Participants:
Blood samples and orbital fibroblasts (OFs) were collected from TAO patients and healthy subjects.
Main Outcome Measures:
Flow cytometry, real-time PCR, cytokine-specific ELISA, and Western blotting were performed.
Results:
Here, we showed a significantly higher proportion of IL-17A-producing T cells in TAO patients and the recruitment of both CD4+ and CD8+ T cells in TAO orbits. TAO orbital tissues expressed more IL-17A receptor, IL-17A, and its related cytokines, with severe fibrotic change compared with normal controls. Furthermore, we validated that IL-17A could enhance the proinflammatory function of OFs and stimulate the production of extracellular matrix proteins in OFs but not eyelid fibroblasts. The mechanisms involved in this enhancement mainly relied on MAPK activation. Finally, we observed that the deubiquitinase inhibitor vialinin A could down-regulate retinoic acid receptor-related orphan receptor-γt expression and decrease IL-17A level in TAO patients.
Conclusion:
Our observations illustrate the potential pathogenic role of IL-17A-producing T cells in the inflammatory response and fibrosis of TAO. The effect of vialinin A on the reduction of retinoic acid receptor-related orphan receptor-γt level implicates its potential role as a novel therapeutic agent for TAO and other autoimmune disorders in the future.
We reported increased IL-17A-producing T cells in TAO. IL-17A was observed to promote inflammation and fibrosis, and vialinin A could decrease IL-17A-producing T cells in TAO by destabilizing RORγt.</description><subject>Case-Control Studies</subject><subject>Cells, Cultured</subject><subject>Chemotaxis, Leukocyte - drug effects</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Fibroblasts - pathology</subject><subject>Fibrosis - chemically induced</subject><subject>Graves Ophthalmopathy - metabolism</subject><subject>Graves Ophthalmopathy - pathology</subject><subject>Humans</subject><subject>Inflammation - chemically induced</subject><subject>Inflammation - metabolism</subject><subject>Inflammation - pathology</subject><subject>Inflammation Mediators - metabolism</subject><subject>Interleukin-17 - metabolism</subject><subject>Interleukin-17 - pharmacology</subject><subject>Orbit - metabolism</subject><subject>Orbit - pathology</subject><subject>T-Lymphocytes - drug effects</subject><subject>T-Lymphocytes - metabolism</subject><subject>Vitamin A - pharmacology</subject><issn>0021-972X</issn><issn>1945-7197</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM9vFCEUx4nR2LX15tlw9CAtv3Zgjpumq002WQ816Y0wDOOyzsAKTNr97wuZ6kkuLzw-75vHB4BPBF8TSvDN0VxTTBpEpKRvwIq0fI0EacVbsMKYEtQK-ngBPqR0xJhwvmbvwQUVlHLa8BVI9ztExAbePWtjY6ezTXDruhiSS7A7wx8xTCE7_wvmg60354dRT5POIZ6h9n3tDXUgOwO3szfZBQ_DAPexc1mPS1o36pQTdB4-bPZX4N2gx2Q_vtZL8HN793D7He323-5vNztkOJEU0RazhmtTFu0JZlKIUgTvbMN6y3FLhB64NIxYXJ60YbLHmrVtw9jQN2bNLsGXJfcUw5_Zpqwml4wdR-1tmJMiErdNUbduCvp1QU35eYp2UKfoJh3PimBVNaujUVWzqpoL_vk1ee4m2_-D_3otAF-ApzBmG9PvcX6yUR2sHvNB4XJ4IySqiViWG6qtmsuWMev7YKLz9hRtSuoY5uiLqv9v8wIvhpgA</recordid><startdate>201608</startdate><enddate>201608</enddate><creator>Fang, Sijie</creator><creator>Huang, Yazhuo</creator><creator>Wang, Shuaiwei</creator><creator>Zhang, Yidan</creator><creator>Luo, Xuerui</creator><creator>Liu, Luyan</creator><creator>Zhong, Sisi</creator><creator>Liu, Xingtong</creator><creator>Li, Dan</creator><creator>Liang, Rui</creator><creator>Miranda, Piccioni</creator><creator>Gu, Ping</creator><creator>Zhou, Huifang</creator><creator>Fan, Xianqun</creator><creator>Li, Bin</creator><general>Endocrine Society</general><general>Copyright by The Endocrine Society</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>7X8</scope></search><sort><creationdate>201608</creationdate><title>IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO</title><author>Fang, Sijie ; Huang, Yazhuo ; Wang, Shuaiwei ; Zhang, Yidan ; Luo, Xuerui ; Liu, Luyan ; Zhong, Sisi ; Liu, Xingtong ; Li, Dan ; Liang, Rui ; Miranda, Piccioni ; Gu, Ping ; Zhou, Huifang ; Fan, Xianqun ; Li, Bin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4182-290364ac426d103877d1074be63de40917af48c31e077dac38d0a399633fd6c53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Case-Control Studies</topic><topic>Cells, Cultured</topic><topic>Chemotaxis, Leukocyte - drug effects</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - metabolism</topic><topic>Fibroblasts - pathology</topic><topic>Fibrosis - chemically induced</topic><topic>Graves Ophthalmopathy - metabolism</topic><topic>Graves Ophthalmopathy - pathology</topic><topic>Humans</topic><topic>Inflammation - chemically induced</topic><topic>Inflammation - metabolism</topic><topic>Inflammation - pathology</topic><topic>Inflammation Mediators - metabolism</topic><topic>Interleukin-17 - metabolism</topic><topic>Interleukin-17 - pharmacology</topic><topic>Orbit - metabolism</topic><topic>Orbit - pathology</topic><topic>T-Lymphocytes - drug effects</topic><topic>T-Lymphocytes - metabolism</topic><topic>Vitamin A - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fang, Sijie</creatorcontrib><creatorcontrib>Huang, Yazhuo</creatorcontrib><creatorcontrib>Wang, Shuaiwei</creatorcontrib><creatorcontrib>Zhang, Yidan</creatorcontrib><creatorcontrib>Luo, Xuerui</creatorcontrib><creatorcontrib>Liu, Luyan</creatorcontrib><creatorcontrib>Zhong, Sisi</creatorcontrib><creatorcontrib>Liu, Xingtong</creatorcontrib><creatorcontrib>Li, Dan</creatorcontrib><creatorcontrib>Liang, Rui</creatorcontrib><creatorcontrib>Miranda, Piccioni</creatorcontrib><creatorcontrib>Gu, Ping</creatorcontrib><creatorcontrib>Zhou, Huifang</creatorcontrib><creatorcontrib>Fan, Xianqun</creatorcontrib><creatorcontrib>Li, Bin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The journal of clinical endocrinology and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fang, Sijie</au><au>Huang, Yazhuo</au><au>Wang, Shuaiwei</au><au>Zhang, Yidan</au><au>Luo, Xuerui</au><au>Liu, Luyan</au><au>Zhong, Sisi</au><au>Liu, Xingtong</au><au>Li, Dan</au><au>Liang, Rui</au><au>Miranda, Piccioni</au><au>Gu, Ping</au><au>Zhou, Huifang</au><au>Fan, Xianqun</au><au>Li, Bin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO</atitle><jtitle>The journal of clinical endocrinology and metabolism</jtitle><addtitle>J Clin Endocrinol Metab</addtitle><date>2016-08</date><risdate>2016</risdate><volume>101</volume><issue>8</issue><spage>2955</spage><epage>2965</epage><pages>2955-2965</pages><issn>0021-972X</issn><eissn>1945-7197</eissn><abstract>Context:
The development of thyroid-associated ophthalmopathy (TAO) is associated with self-immune dysfunction. Recent findings in TAO and Graves' disease indicate that IL-17A may also be involved in the autoimmunity of TAO.
Objective:
We sought to investigate the pathogenic function of IL-17A-producing T cells in TAO.
Design/Setting/Participants:
Blood samples and orbital fibroblasts (OFs) were collected from TAO patients and healthy subjects.
Main Outcome Measures:
Flow cytometry, real-time PCR, cytokine-specific ELISA, and Western blotting were performed.
Results:
Here, we showed a significantly higher proportion of IL-17A-producing T cells in TAO patients and the recruitment of both CD4+ and CD8+ T cells in TAO orbits. TAO orbital tissues expressed more IL-17A receptor, IL-17A, and its related cytokines, with severe fibrotic change compared with normal controls. Furthermore, we validated that IL-17A could enhance the proinflammatory function of OFs and stimulate the production of extracellular matrix proteins in OFs but not eyelid fibroblasts. The mechanisms involved in this enhancement mainly relied on MAPK activation. Finally, we observed that the deubiquitinase inhibitor vialinin A could down-regulate retinoic acid receptor-related orphan receptor-γt expression and decrease IL-17A level in TAO patients.
Conclusion:
Our observations illustrate the potential pathogenic role of IL-17A-producing T cells in the inflammatory response and fibrosis of TAO. The effect of vialinin A on the reduction of retinoic acid receptor-related orphan receptor-γt level implicates its potential role as a novel therapeutic agent for TAO and other autoimmune disorders in the future.
We reported increased IL-17A-producing T cells in TAO. IL-17A was observed to promote inflammation and fibrosis, and vialinin A could decrease IL-17A-producing T cells in TAO by destabilizing RORγt.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>27224264</pmid><doi>10.1210/jc.2016-1882</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0021-972X |
| ispartof | The journal of clinical endocrinology and metabolism, 2016-08, Vol.101 (8), p.2955-2965 |
| issn | 0021-972X 1945-7197 |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection; Journals@Ovid Complete |
| subjects | Case-Control Studies Cells, Cultured Chemotaxis, Leukocyte - drug effects Fibroblasts - drug effects Fibroblasts - metabolism Fibroblasts - pathology Fibrosis - chemically induced Graves Ophthalmopathy - metabolism Graves Ophthalmopathy - pathology Humans Inflammation - chemically induced Inflammation - metabolism Inflammation - pathology Inflammation Mediators - metabolism Interleukin-17 - metabolism Interleukin-17 - pharmacology Orbit - metabolism Orbit - pathology T-Lymphocytes - drug effects T-Lymphocytes - metabolism Vitamin A - pharmacology |
| title | IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO |
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