Synovial IL‐21/TNF‐producing CD4+ T cells induce joint destruction in rheumatoid arthritis by inducing matrix metalloproteinase production by fibroblast‐like synoviocytes
Synovial IL‐21+TNF+CD4+ T cells induce matrix metalloproteinase production by fibroblast‐like synoviocytes in RA patients. Bone and cartilage destruction is one of the key manifestations of rheumatoid arthritis (RA). Although the role of T helper (Th)17 cells in these processes is clear, the role of...
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| Veröffentlicht in: | Journal of leukocyte biology 2017-03, Vol.101 (3), p.775-783 |
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| creator | Lebre, Maria C. Vieira, Pedro L. Tang, Man Wai Aarrass, Saïda Helder, Boy Newsom‐Davis, Thomas Tak, Paul P. Screaton, Gavin R. |
| description | Synovial IL‐21+TNF+CD4+ T cells induce matrix metalloproteinase production by fibroblast‐like synoviocytes in RA patients.
Bone and cartilage destruction is one of the key manifestations of rheumatoid arthritis (RA). Although the role of T helper (Th)17 cells in these processes is clear, the role of IL‐21–producing cells T cells has been neglected. We sought to investigate the role of IL‐21 in RA by focusing on the functional characteristics of the main producers of this cytokine, synovial CD4+IL‐21+ T cells. We show that the frequency of both synovial fluid (SF) CD4+IL‐21+ or CD4+IL‐21+TNF+ T cells in patients with RA was significantly higher compared with patients with psoriatic arthritis (PsA). The frequency of peripheral blood (PB) IL‐21+CD4+ T cells in patients with RA positively correlated with disease activity score 28 (DAS28), serum anticyclic citrullinated peptide (anti‐CCP) antibodies and IgM‐rheumatoid factor (IgM‐RF). IL‐21 levels in RA SF were associated with matrix metalloproteinase (MMP)‐1 and MMP‐3. Related to this, IL‐21 induced significantly the secretion of MMP‐1 and MMP‐3 in RA synovial biopsies. Sorted SF CD4+IL‐21+ T cells significantly induced the release of MMP‐1 and MMP‐3 by fibroblast‐like synoviocytes (FLS) compared with medium or CD4+IL‐21− T cells in a coculture system. Neutralization of both IL‐21 and TNF resulted in significantly less production of MMP by FLS. The results of this study indicate a new role for synovial CD4+IL‐21+TNF+ T cells in promoting synovial inflammation/joint destruction in patients with RA. Importantly, IL‐21 blockade in combination with anti‐TNF might be an effective therapy in patients with RA by inhibiting MMP‐induced inflammation/joint destruction. |
| doi_str_mv | 10.1189/jlb.5A0516-217RR |
| format | Article |
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Bone and cartilage destruction is one of the key manifestations of rheumatoid arthritis (RA). Although the role of T helper (Th)17 cells in these processes is clear, the role of IL‐21–producing cells T cells has been neglected. We sought to investigate the role of IL‐21 in RA by focusing on the functional characteristics of the main producers of this cytokine, synovial CD4+IL‐21+ T cells. We show that the frequency of both synovial fluid (SF) CD4+IL‐21+ or CD4+IL‐21+TNF+ T cells in patients with RA was significantly higher compared with patients with psoriatic arthritis (PsA). The frequency of peripheral blood (PB) IL‐21+CD4+ T cells in patients with RA positively correlated with disease activity score 28 (DAS28), serum anticyclic citrullinated peptide (anti‐CCP) antibodies and IgM‐rheumatoid factor (IgM‐RF). IL‐21 levels in RA SF were associated with matrix metalloproteinase (MMP)‐1 and MMP‐3. Related to this, IL‐21 induced significantly the secretion of MMP‐1 and MMP‐3 in RA synovial biopsies. Sorted SF CD4+IL‐21+ T cells significantly induced the release of MMP‐1 and MMP‐3 by fibroblast‐like synoviocytes (FLS) compared with medium or CD4+IL‐21− T cells in a coculture system. Neutralization of both IL‐21 and TNF resulted in significantly less production of MMP by FLS. The results of this study indicate a new role for synovial CD4+IL‐21+TNF+ T cells in promoting synovial inflammation/joint destruction in patients with RA. Importantly, IL‐21 blockade in combination with anti‐TNF might be an effective therapy in patients with RA by inhibiting MMP‐induced inflammation/joint destruction.</description><identifier>ISSN: 0741-5400</identifier><identifier>EISSN: 1938-3673</identifier><identifier>DOI: 10.1189/jlb.5A0516-217RR</identifier><identifier>PMID: 27733582</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Antibodies ; Arthritis ; Arthritis, Rheumatoid - immunology ; Arthritis, Rheumatoid - pathology ; autoimmune ; Biopsy ; Cartilage ; CD4 antigen ; CD4-Positive T-Lymphocytes - immunology ; Cell Proliferation ; Citrulline ; Destruction ; Fibroblasts ; Fibroblasts - pathology ; Health risk assessment ; Humans ; Immunoglobulin M ; Immunoglobulin M - metabolism ; inflammation ; Interferon-gamma - metabolism ; Interleukin 21 ; Interleukin-17 - metabolism ; Interleukin-22 ; Interleukin-6 - metabolism ; Interleukins - metabolism ; Interstitial collagenase ; Joints - pathology ; Lymphocytes ; Lymphocytes T ; Matrix metalloproteinase ; Matrix Metalloproteinase 1 - metabolism ; Matrix Metalloproteinase 3 - metabolism ; Metalloproteinase ; Neutralization ; Patients ; Peptides, Cyclic - metabolism ; Peripheral blood ; Proto-Oncogene Proteins c-bcl-6 - metabolism ; Psoriasis - immunology ; Psoriasis - pathology ; Psoriatic arthritis ; RANK Ligand - metabolism ; Rheumatoid arthritis ; Rheumatoid factor ; Rheumatoid Factor - metabolism ; Stromelysin 1 ; Synovial fluid ; Synovial Fluid - metabolism ; Synoviocytes ; Synoviocytes - metabolism ; T-Box Domain Proteins - metabolism ; T-Lymphocytes, Helper-Inducer - immunology ; Tumor necrosis factor ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>Journal of leukocyte biology, 2017-03, Vol.101 (3), p.775-783</ispartof><rights>2017 Society for Leukocyte Biology</rights><rights>Society for Leukocyte Biology.</rights><rights>Copyright Federation of American Societies for Experimental Biology (FASEB) Mar 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4955-259ddb87197b61b9eb0e875f7f246023c0894d42b2e6e10d72d101d1e8dedc6a3</citedby><cites>FETCH-LOGICAL-c4955-259ddb87197b61b9eb0e875f7f246023c0894d42b2e6e10d72d101d1e8dedc6a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1189%2Fjlb.5A0516-217RR$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1189%2Fjlb.5A0516-217RR$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27733582$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lebre, Maria C.</creatorcontrib><creatorcontrib>Vieira, Pedro L.</creatorcontrib><creatorcontrib>Tang, Man Wai</creatorcontrib><creatorcontrib>Aarrass, Saïda</creatorcontrib><creatorcontrib>Helder, Boy</creatorcontrib><creatorcontrib>Newsom‐Davis, Thomas</creatorcontrib><creatorcontrib>Tak, Paul P.</creatorcontrib><creatorcontrib>Screaton, Gavin R.</creatorcontrib><title>Synovial IL‐21/TNF‐producing CD4+ T cells induce joint destruction in rheumatoid arthritis by inducing matrix metalloproteinase production by fibroblast‐like synoviocytes</title><title>Journal of leukocyte biology</title><addtitle>J Leukoc Biol</addtitle><description>Synovial IL‐21+TNF+CD4+ T cells induce matrix metalloproteinase production by fibroblast‐like synoviocytes in RA patients.
Bone and cartilage destruction is one of the key manifestations of rheumatoid arthritis (RA). Although the role of T helper (Th)17 cells in these processes is clear, the role of IL‐21–producing cells T cells has been neglected. We sought to investigate the role of IL‐21 in RA by focusing on the functional characteristics of the main producers of this cytokine, synovial CD4+IL‐21+ T cells. We show that the frequency of both synovial fluid (SF) CD4+IL‐21+ or CD4+IL‐21+TNF+ T cells in patients with RA was significantly higher compared with patients with psoriatic arthritis (PsA). The frequency of peripheral blood (PB) IL‐21+CD4+ T cells in patients with RA positively correlated with disease activity score 28 (DAS28), serum anticyclic citrullinated peptide (anti‐CCP) antibodies and IgM‐rheumatoid factor (IgM‐RF). IL‐21 levels in RA SF were associated with matrix metalloproteinase (MMP)‐1 and MMP‐3. Related to this, IL‐21 induced significantly the secretion of MMP‐1 and MMP‐3 in RA synovial biopsies. Sorted SF CD4+IL‐21+ T cells significantly induced the release of MMP‐1 and MMP‐3 by fibroblast‐like synoviocytes (FLS) compared with medium or CD4+IL‐21− T cells in a coculture system. Neutralization of both IL‐21 and TNF resulted in significantly less production of MMP by FLS. The results of this study indicate a new role for synovial CD4+IL‐21+TNF+ T cells in promoting synovial inflammation/joint destruction in patients with RA. Importantly, IL‐21 blockade in combination with anti‐TNF might be an effective therapy in patients with RA by inhibiting MMP‐induced inflammation/joint destruction.</description><subject>Antibodies</subject><subject>Arthritis</subject><subject>Arthritis, Rheumatoid - immunology</subject><subject>Arthritis, Rheumatoid - pathology</subject><subject>autoimmune</subject><subject>Biopsy</subject><subject>Cartilage</subject><subject>CD4 antigen</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>Cell Proliferation</subject><subject>Citrulline</subject><subject>Destruction</subject><subject>Fibroblasts</subject><subject>Fibroblasts - pathology</subject><subject>Health risk assessment</subject><subject>Humans</subject><subject>Immunoglobulin M</subject><subject>Immunoglobulin M - metabolism</subject><subject>inflammation</subject><subject>Interferon-gamma - metabolism</subject><subject>Interleukin 21</subject><subject>Interleukin-17 - metabolism</subject><subject>Interleukin-22</subject><subject>Interleukin-6 - metabolism</subject><subject>Interleukins - metabolism</subject><subject>Interstitial collagenase</subject><subject>Joints - pathology</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Matrix metalloproteinase</subject><subject>Matrix Metalloproteinase 1 - metabolism</subject><subject>Matrix Metalloproteinase 3 - metabolism</subject><subject>Metalloproteinase</subject><subject>Neutralization</subject><subject>Patients</subject><subject>Peptides, Cyclic - metabolism</subject><subject>Peripheral blood</subject><subject>Proto-Oncogene Proteins c-bcl-6 - metabolism</subject><subject>Psoriasis - immunology</subject><subject>Psoriasis - pathology</subject><subject>Psoriatic arthritis</subject><subject>RANK Ligand - metabolism</subject><subject>Rheumatoid arthritis</subject><subject>Rheumatoid factor</subject><subject>Rheumatoid Factor - metabolism</subject><subject>Stromelysin 1</subject><subject>Synovial fluid</subject><subject>Synovial Fluid - metabolism</subject><subject>Synoviocytes</subject><subject>Synoviocytes - metabolism</subject><subject>T-Box Domain Proteins - metabolism</subject><subject>T-Lymphocytes, Helper-Inducer - immunology</subject><subject>Tumor necrosis factor</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>0741-5400</issn><issn>1938-3673</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1u1DAUhS0EokNhzwpZYoOE0vo3dpZloFA0AqkMa8uOHerBiYudANnxCDwKz8ST4JkUFmxgZcv3u-ee6wPAQ4xOMJbN6S6YE36GOK4rgsXl5S2wwg2VFa0FvQ1WSDBccYbQEbiX8w4hREmN7oIjIgSlXJIV-PFuHuJnrwO82Pz89p3g0-2b83K5TtFOrR8-wPVz9hRuYetCyNAP5dXBXfTDCK3LY5ra0cehFGC6clOvx-gt1Gm8Sn70GZp56dkrlWLyX2HvRh1CLBNG5wedHVyGHXQK33mTogk6j8VH8B8dzAePsZ1Hl--DO50O2T24OY_B-_MX2_WravP25cX6bFO1rOG8Iryx1kiBG2FqbBpnkJOCd6IjrEaEtkg2zDJiiKsdRlYQixG22EnrbFtregyeLLrF3KepbKp6n_efoAcXp6ywFEISxDD6D5RyhjlHTUEf_4Xu4pSGsojCjaSMcipYodBCtSnmnFynrpPvdZoVRmofvCrBqyV4dQi-tDy6EZ5M7-yfht9JF4AvwBcf3PxPQfV68wwJwekvKLW_5w</recordid><startdate>201703</startdate><enddate>201703</enddate><creator>Lebre, Maria C.</creator><creator>Vieira, Pedro L.</creator><creator>Tang, Man Wai</creator><creator>Aarrass, Saïda</creator><creator>Helder, Boy</creator><creator>Newsom‐Davis, Thomas</creator><creator>Tak, Paul P.</creator><creator>Screaton, Gavin R.</creator><general>Oxford University Press</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>7QL</scope><scope>7T5</scope><scope>7T7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>201703</creationdate><title>Synovial IL‐21/TNF‐producing CD4+ T cells induce joint destruction in rheumatoid arthritis by inducing matrix metalloproteinase production by fibroblast‐like synoviocytes</title><author>Lebre, Maria C. ; Vieira, Pedro L. ; Tang, Man Wai ; Aarrass, Saïda ; Helder, Boy ; Newsom‐Davis, Thomas ; Tak, Paul P. ; Screaton, Gavin R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4955-259ddb87197b61b9eb0e875f7f246023c0894d42b2e6e10d72d101d1e8dedc6a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Antibodies</topic><topic>Arthritis</topic><topic>Arthritis, Rheumatoid - immunology</topic><topic>Arthritis, Rheumatoid - pathology</topic><topic>autoimmune</topic><topic>Biopsy</topic><topic>Cartilage</topic><topic>CD4 antigen</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>Cell Proliferation</topic><topic>Citrulline</topic><topic>Destruction</topic><topic>Fibroblasts</topic><topic>Fibroblasts - pathology</topic><topic>Health risk assessment</topic><topic>Humans</topic><topic>Immunoglobulin M</topic><topic>Immunoglobulin M - metabolism</topic><topic>inflammation</topic><topic>Interferon-gamma - metabolism</topic><topic>Interleukin 21</topic><topic>Interleukin-17 - metabolism</topic><topic>Interleukin-22</topic><topic>Interleukin-6 - metabolism</topic><topic>Interleukins - metabolism</topic><topic>Interstitial collagenase</topic><topic>Joints - pathology</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Matrix metalloproteinase</topic><topic>Matrix Metalloproteinase 1 - metabolism</topic><topic>Matrix Metalloproteinase 3 - metabolism</topic><topic>Metalloproteinase</topic><topic>Neutralization</topic><topic>Patients</topic><topic>Peptides, Cyclic - metabolism</topic><topic>Peripheral blood</topic><topic>Proto-Oncogene Proteins c-bcl-6 - metabolism</topic><topic>Psoriasis - immunology</topic><topic>Psoriasis - pathology</topic><topic>Psoriatic arthritis</topic><topic>RANK Ligand - metabolism</topic><topic>Rheumatoid arthritis</topic><topic>Rheumatoid factor</topic><topic>Rheumatoid Factor - metabolism</topic><topic>Stromelysin 1</topic><topic>Synovial fluid</topic><topic>Synovial Fluid - metabolism</topic><topic>Synoviocytes</topic><topic>Synoviocytes - metabolism</topic><topic>T-Box Domain Proteins - metabolism</topic><topic>T-Lymphocytes, Helper-Inducer - immunology</topic><topic>Tumor necrosis factor</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lebre, Maria C.</creatorcontrib><creatorcontrib>Vieira, Pedro L.</creatorcontrib><creatorcontrib>Tang, Man Wai</creatorcontrib><creatorcontrib>Aarrass, Saïda</creatorcontrib><creatorcontrib>Helder, Boy</creatorcontrib><creatorcontrib>Newsom‐Davis, Thomas</creatorcontrib><creatorcontrib>Tak, Paul P.</creatorcontrib><creatorcontrib>Screaton, Gavin R.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of leukocyte biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lebre, Maria C.</au><au>Vieira, Pedro L.</au><au>Tang, Man Wai</au><au>Aarrass, Saïda</au><au>Helder, Boy</au><au>Newsom‐Davis, Thomas</au><au>Tak, Paul P.</au><au>Screaton, Gavin R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synovial IL‐21/TNF‐producing CD4+ T cells induce joint destruction in rheumatoid arthritis by inducing matrix metalloproteinase production by fibroblast‐like synoviocytes</atitle><jtitle>Journal of leukocyte biology</jtitle><addtitle>J Leukoc Biol</addtitle><date>2017-03</date><risdate>2017</risdate><volume>101</volume><issue>3</issue><spage>775</spage><epage>783</epage><pages>775-783</pages><issn>0741-5400</issn><eissn>1938-3673</eissn><abstract>Synovial IL‐21+TNF+CD4+ T cells induce matrix metalloproteinase production by fibroblast‐like synoviocytes in RA patients.
Bone and cartilage destruction is one of the key manifestations of rheumatoid arthritis (RA). Although the role of T helper (Th)17 cells in these processes is clear, the role of IL‐21–producing cells T cells has been neglected. We sought to investigate the role of IL‐21 in RA by focusing on the functional characteristics of the main producers of this cytokine, synovial CD4+IL‐21+ T cells. We show that the frequency of both synovial fluid (SF) CD4+IL‐21+ or CD4+IL‐21+TNF+ T cells in patients with RA was significantly higher compared with patients with psoriatic arthritis (PsA). The frequency of peripheral blood (PB) IL‐21+CD4+ T cells in patients with RA positively correlated with disease activity score 28 (DAS28), serum anticyclic citrullinated peptide (anti‐CCP) antibodies and IgM‐rheumatoid factor (IgM‐RF). IL‐21 levels in RA SF were associated with matrix metalloproteinase (MMP)‐1 and MMP‐3. Related to this, IL‐21 induced significantly the secretion of MMP‐1 and MMP‐3 in RA synovial biopsies. Sorted SF CD4+IL‐21+ T cells significantly induced the release of MMP‐1 and MMP‐3 by fibroblast‐like synoviocytes (FLS) compared with medium or CD4+IL‐21− T cells in a coculture system. Neutralization of both IL‐21 and TNF resulted in significantly less production of MMP by FLS. The results of this study indicate a new role for synovial CD4+IL‐21+TNF+ T cells in promoting synovial inflammation/joint destruction in patients with RA. Importantly, IL‐21 blockade in combination with anti‐TNF might be an effective therapy in patients with RA by inhibiting MMP‐induced inflammation/joint destruction.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>27733582</pmid><doi>10.1189/jlb.5A0516-217RR</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antibodies Arthritis Arthritis, Rheumatoid - immunology Arthritis, Rheumatoid - pathology autoimmune Biopsy Cartilage CD4 antigen CD4-Positive T-Lymphocytes - immunology Cell Proliferation Citrulline Destruction Fibroblasts Fibroblasts - pathology Health risk assessment Humans Immunoglobulin M Immunoglobulin M - metabolism inflammation Interferon-gamma - metabolism Interleukin 21 Interleukin-17 - metabolism Interleukin-22 Interleukin-6 - metabolism Interleukins - metabolism Interstitial collagenase Joints - pathology Lymphocytes Lymphocytes T Matrix metalloproteinase Matrix Metalloproteinase 1 - metabolism Matrix Metalloproteinase 3 - metabolism Metalloproteinase Neutralization Patients Peptides, Cyclic - metabolism Peripheral blood Proto-Oncogene Proteins c-bcl-6 - metabolism Psoriasis - immunology Psoriasis - pathology Psoriatic arthritis RANK Ligand - metabolism Rheumatoid arthritis Rheumatoid factor Rheumatoid Factor - metabolism Stromelysin 1 Synovial fluid Synovial Fluid - metabolism Synoviocytes Synoviocytes - metabolism T-Box Domain Proteins - metabolism T-Lymphocytes, Helper-Inducer - immunology Tumor necrosis factor Tumor Necrosis Factor-alpha - metabolism |
| title | Synovial IL‐21/TNF‐producing CD4+ T cells induce joint destruction in rheumatoid arthritis by inducing matrix metalloproteinase production by fibroblast‐like synoviocytes |
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