Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis
Interleukin (IL)-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines. However, the role of the IL-18/IL-18 receptor-alpha (Rα) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18Rα knockout (KO) m...
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| Veröffentlicht in: | Cells (Basel, Switzerland) Switzerland), 2019-12, Vol.9 (1), p.11 |
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| creator | Nozaki, Yuji Ri, Jinhai Sakai, Kenji Niki, Kaoru Kinoshita, Koji Funauchi, Masanori Matsumura, Itaru |
| description | Interleukin (IL)-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines. However, the role of the IL-18/IL-18 receptor-alpha (Rα) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18Rα knockout (KO) mice were immunized with bovine type II collagen before the onset of arthritis induced by lipopolysaccharide injection. Disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum inflammatory cytokine and anticollagen antibody levels were quantified by an enzyme-linked immunosorbent assay. Joint cytokine and matrix metalloproteinases-3 levels were determined by a quantitative polymerase chain reaction. Splenic suppressors of cytokine signaling (SOCS) were determined by Western blot analysis as indices of systemic immunoresponse. IL-18Rα KO mice showed lower arthritis and histological scores in bone erosion and synovitis due to reductions in the infiltration of CD4+ T cells and F4/80+ cells and decreased serum IL-6, -18, TNF, and IFN-γ levels. The mRNA expression and protein levels of SOCS3 were significantly increased in the IL-18Rα KO mice. By an up-regulation of SOCS, pro-inflammatory cytokines were decreased through the IL-18/IL-18Rα signaling pathway. These results suggest that inhibitors of the IL-18/IL-18Rα signaling pathway could become new therapeutic agents for rheumatoid arthritis. |
| doi_str_mv | 10.3390/cells9010011 |
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However, the role of the IL-18/IL-18 receptor-alpha (Rα) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18Rα knockout (KO) mice were immunized with bovine type II collagen before the onset of arthritis induced by lipopolysaccharide injection. Disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum inflammatory cytokine and anticollagen antibody levels were quantified by an enzyme-linked immunosorbent assay. Joint cytokine and matrix metalloproteinases-3 levels were determined by a quantitative polymerase chain reaction. Splenic suppressors of cytokine signaling (SOCS) were determined by Western blot analysis as indices of systemic immunoresponse. IL-18Rα KO mice showed lower arthritis and histological scores in bone erosion and synovitis due to reductions in the infiltration of CD4+ T cells and F4/80+ cells and decreased serum IL-6, -18, TNF, and IFN-γ levels. The mRNA expression and protein levels of SOCS3 were significantly increased in the IL-18Rα KO mice. By an up-regulation of SOCS, pro-inflammatory cytokines were decreased through the IL-18/IL-18Rα signaling pathway. These results suggest that inhibitors of the IL-18/IL-18Rα signaling pathway could become new therapeutic agents for rheumatoid arthritis.</description><identifier>ISSN: 2073-4409</identifier><identifier>EISSN: 2073-4409</identifier><identifier>DOI: 10.3390/cells9010011</identifier><identifier>PMID: 31861496</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Animal models ; Animals ; Arthritis, Rheumatoid - blood ; Arthritis, Rheumatoid - immunology ; Cartilage ; CD4 antigen ; CD4-Positive T-Lymphocytes - immunology ; Cell growth ; Collagen ; Collagen (type II) ; Cytokines ; Cytokines - blood ; Cytokines - immunology ; Disease Models, Animal ; Enzyme-linked immunosorbent assay ; Experiments ; Female ; Gene expression ; Government agencies ; Inflammation ; Interferon-gamma - immunology ; Interleukin 18 ; Interleukin 18 receptors ; Interleukin 6 ; Interleukin-18 - biosynthesis ; Interleukin-18 - genetics ; Interleukin-18 - immunology ; Interleukin-18 Receptor alpha Subunit - antagonists & inhibitors ; Interleukin-18 Receptor alpha Subunit - biosynthesis ; Interleukin-18 Receptor alpha Subunit - genetics ; Interleukin-18 Receptor alpha Subunit - immunology ; Kinases ; Laboratory animals ; Lipopolysaccharides ; Lipopolysaccharides - pharmacology ; Lymph Nodes - immunology ; Lymphocytes ; Lymphocytes T ; Male ; Matrix metalloproteinase ; Medical research ; Mice ; Mice, Inbred DBA ; Mice, Knockout ; Polymerase chain reaction ; Rheumatoid arthritis ; RNA, Messenger - biosynthesis ; RNA, Messenger - genetics ; Signal transduction ; Signal Transduction - immunology ; Spleen ; Spleen - immunology ; Suppressor of Cytokine Signaling 3 Protein - biosynthesis ; Suppressor of Cytokine Signaling 3 Protein - genetics ; Suppressor of Cytokine Signaling 3 Protein - immunology ; Synovitis ; Tumor necrosis factor ; Tumor necrosis factor-TNF ; γ-Interferon</subject><ispartof>Cells (Basel, Switzerland), 2019-12, Vol.9 (1), p.11</ispartof><rights>2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 by the authors. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c548t-246142737fd6574cbad8a880221aaf4514059fdb931ec3f271927a32c5ad2ee93</citedby><cites>FETCH-LOGICAL-c548t-246142737fd6574cbad8a880221aaf4514059fdb931ec3f271927a32c5ad2ee93</cites><orcidid>0000-0003-2810-1519</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/PMC7017073/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017073/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,53770,53772</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31861496$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nozaki, Yuji</creatorcontrib><creatorcontrib>Ri, Jinhai</creatorcontrib><creatorcontrib>Sakai, Kenji</creatorcontrib><creatorcontrib>Niki, Kaoru</creatorcontrib><creatorcontrib>Kinoshita, Koji</creatorcontrib><creatorcontrib>Funauchi, Masanori</creatorcontrib><creatorcontrib>Matsumura, Itaru</creatorcontrib><title>Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis</title><title>Cells (Basel, Switzerland)</title><addtitle>Cells</addtitle><description>Interleukin (IL)-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines. However, the role of the IL-18/IL-18 receptor-alpha (Rα) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18Rα knockout (KO) mice were immunized with bovine type II collagen before the onset of arthritis induced by lipopolysaccharide injection. Disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum inflammatory cytokine and anticollagen antibody levels were quantified by an enzyme-linked immunosorbent assay. Joint cytokine and matrix metalloproteinases-3 levels were determined by a quantitative polymerase chain reaction. Splenic suppressors of cytokine signaling (SOCS) were determined by Western blot analysis as indices of systemic immunoresponse. IL-18Rα KO mice showed lower arthritis and histological scores in bone erosion and synovitis due to reductions in the infiltration of CD4+ T cells and F4/80+ cells and decreased serum IL-6, -18, TNF, and IFN-γ levels. The mRNA expression and protein levels of SOCS3 were significantly increased in the IL-18Rα KO mice. By an up-regulation of SOCS, pro-inflammatory cytokines were decreased through the IL-18/IL-18Rα signaling pathway. These results suggest that inhibitors of the IL-18/IL-18Rα signaling pathway could become new therapeutic agents for rheumatoid arthritis.</description><subject>Animal models</subject><subject>Animals</subject><subject>Arthritis, Rheumatoid - blood</subject><subject>Arthritis, Rheumatoid - immunology</subject><subject>Cartilage</subject><subject>CD4 antigen</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>Cell growth</subject><subject>Collagen</subject><subject>Collagen (type II)</subject><subject>Cytokines</subject><subject>Cytokines - blood</subject><subject>Cytokines - immunology</subject><subject>Disease Models, Animal</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Experiments</subject><subject>Female</subject><subject>Gene expression</subject><subject>Government agencies</subject><subject>Inflammation</subject><subject>Interferon-gamma - immunology</subject><subject>Interleukin 18</subject><subject>Interleukin 18 receptors</subject><subject>Interleukin 6</subject><subject>Interleukin-18 - 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genetics</subject><subject>Signal transduction</subject><subject>Signal Transduction - immunology</subject><subject>Spleen</subject><subject>Spleen - immunology</subject><subject>Suppressor of Cytokine Signaling 3 Protein - biosynthesis</subject><subject>Suppressor of Cytokine Signaling 3 Protein - genetics</subject><subject>Suppressor of Cytokine Signaling 3 Protein - immunology</subject><subject>Synovitis</subject><subject>Tumor necrosis factor</subject><subject>Tumor necrosis factor-TNF</subject><subject>γ-Interferon</subject><issn>2073-4409</issn><issn>2073-4409</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpdkc1v1DAQxS0EolXpjTOyxIUDAX8lji9Iq1Jgpa1ABc7WbDLZuErsxXZA_e_rVUu14IstzU_Pb94j5CVn76Q07H2H05QM44xx_oScCqZlpRQzT4_eJ-Q8pRtWTssbzurn5ETytuHKNKdkv_aj27rsgqdhoHlEut5UvKXX2OE-h0i_u52Hyfkd_QZ5_AO3dDXj5EKEjIl-dAkhIXWeAr1aovNIr0KP00HtesRlhhxcT1cxj7F8k16QZwNMCc8f7jPy89Plj4sv1ebr5_XFalN1tWpzJVQxKLTUQ9_UWnVb6FtoWyYEBxhUzRWrzdBvjeTYyUFoboQGKboaeoFo5Bn5cK-7X7Yz9h36HGGy--hmiLc2gLP_Trwb7S78tppxXaIrAm8eBGL4tWDKdnbpkDd4DEuyQgpT_GlRF_T1f-hNWGJJrVBlG6mkanSh3t5TXQwpRRwezXBmD23a4zYL_up4gUf4b3fyDtwMmww</recordid><startdate>20191218</startdate><enddate>20191218</enddate><creator>Nozaki, Yuji</creator><creator>Ri, Jinhai</creator><creator>Sakai, Kenji</creator><creator>Niki, Kaoru</creator><creator>Kinoshita, Koji</creator><creator>Funauchi, Masanori</creator><creator>Matsumura, Itaru</creator><general>MDPI AG</general><general>MDPI</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>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2810-1519</orcidid></search><sort><creationdate>20191218</creationdate><title>Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis</title><author>Nozaki, Yuji ; Ri, Jinhai ; Sakai, Kenji ; Niki, Kaoru ; Kinoshita, Koji ; Funauchi, Masanori ; Matsumura, Itaru</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c548t-246142737fd6574cbad8a880221aaf4514059fdb931ec3f271927a32c5ad2ee93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Arthritis, Rheumatoid - blood</topic><topic>Arthritis, Rheumatoid - immunology</topic><topic>Cartilage</topic><topic>CD4 antigen</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>Cell growth</topic><topic>Collagen</topic><topic>Collagen (type II)</topic><topic>Cytokines</topic><topic>Cytokines - blood</topic><topic>Cytokines - immunology</topic><topic>Disease Models, Animal</topic><topic>Enzyme-linked immunosorbent assay</topic><topic>Experiments</topic><topic>Female</topic><topic>Gene expression</topic><topic>Government agencies</topic><topic>Inflammation</topic><topic>Interferon-gamma - immunology</topic><topic>Interleukin 18</topic><topic>Interleukin 18 receptors</topic><topic>Interleukin 6</topic><topic>Interleukin-18 - biosynthesis</topic><topic>Interleukin-18 - genetics</topic><topic>Interleukin-18 - immunology</topic><topic>Interleukin-18 Receptor alpha Subunit - antagonists & inhibitors</topic><topic>Interleukin-18 Receptor alpha Subunit - biosynthesis</topic><topic>Interleukin-18 Receptor alpha Subunit - genetics</topic><topic>Interleukin-18 Receptor alpha Subunit - immunology</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>Lipopolysaccharides</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Lymph Nodes - immunology</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Male</topic><topic>Matrix metalloproteinase</topic><topic>Medical research</topic><topic>Mice</topic><topic>Mice, Inbred DBA</topic><topic>Mice, Knockout</topic><topic>Polymerase chain reaction</topic><topic>Rheumatoid arthritis</topic><topic>RNA, Messenger - biosynthesis</topic><topic>RNA, Messenger - genetics</topic><topic>Signal transduction</topic><topic>Signal Transduction - immunology</topic><topic>Spleen</topic><topic>Spleen - immunology</topic><topic>Suppressor of Cytokine Signaling 3 Protein - biosynthesis</topic><topic>Suppressor of Cytokine Signaling 3 Protein - genetics</topic><topic>Suppressor of Cytokine Signaling 3 Protein - immunology</topic><topic>Synovitis</topic><topic>Tumor necrosis factor</topic><topic>Tumor necrosis factor-TNF</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nozaki, Yuji</creatorcontrib><creatorcontrib>Ri, Jinhai</creatorcontrib><creatorcontrib>Sakai, Kenji</creatorcontrib><creatorcontrib>Niki, Kaoru</creatorcontrib><creatorcontrib>Kinoshita, Koji</creatorcontrib><creatorcontrib>Funauchi, Masanori</creatorcontrib><creatorcontrib>Matsumura, Itaru</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>ProQuest Biological Science Journals</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content (ProQuest)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cells (Basel, Switzerland)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nozaki, Yuji</au><au>Ri, Jinhai</au><au>Sakai, Kenji</au><au>Niki, Kaoru</au><au>Kinoshita, Koji</au><au>Funauchi, Masanori</au><au>Matsumura, Itaru</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis</atitle><jtitle>Cells (Basel, Switzerland)</jtitle><addtitle>Cells</addtitle><date>2019-12-18</date><risdate>2019</risdate><volume>9</volume><issue>1</issue><spage>11</spage><pages>11-</pages><issn>2073-4409</issn><eissn>2073-4409</eissn><abstract>Interleukin (IL)-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines. However, the role of the IL-18/IL-18 receptor-alpha (Rα) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18Rα knockout (KO) mice were immunized with bovine type II collagen before the onset of arthritis induced by lipopolysaccharide injection. Disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum inflammatory cytokine and anticollagen antibody levels were quantified by an enzyme-linked immunosorbent assay. Joint cytokine and matrix metalloproteinases-3 levels were determined by a quantitative polymerase chain reaction. Splenic suppressors of cytokine signaling (SOCS) were determined by Western blot analysis as indices of systemic immunoresponse. IL-18Rα KO mice showed lower arthritis and histological scores in bone erosion and synovitis due to reductions in the infiltration of CD4+ T cells and F4/80+ cells and decreased serum IL-6, -18, TNF, and IFN-γ levels. The mRNA expression and protein levels of SOCS3 were significantly increased in the IL-18Rα KO mice. By an up-regulation of SOCS, pro-inflammatory cytokines were decreased through the IL-18/IL-18Rα signaling pathway. These results suggest that inhibitors of the IL-18/IL-18Rα signaling pathway could become new therapeutic agents for rheumatoid arthritis.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>31861496</pmid><doi>10.3390/cells9010011</doi><orcidid>https://orcid.org/0000-0003-2810-1519</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animal models Animals Arthritis, Rheumatoid - blood Arthritis, Rheumatoid - immunology Cartilage CD4 antigen CD4-Positive T-Lymphocytes - immunology Cell growth Collagen Collagen (type II) Cytokines Cytokines - blood Cytokines - immunology Disease Models, Animal Enzyme-linked immunosorbent assay Experiments Female Gene expression Government agencies Inflammation Interferon-gamma - immunology Interleukin 18 Interleukin 18 receptors Interleukin 6 Interleukin-18 - biosynthesis Interleukin-18 - genetics Interleukin-18 - immunology Interleukin-18 Receptor alpha Subunit - antagonists & inhibitors Interleukin-18 Receptor alpha Subunit - biosynthesis Interleukin-18 Receptor alpha Subunit - genetics Interleukin-18 Receptor alpha Subunit - immunology Kinases Laboratory animals Lipopolysaccharides Lipopolysaccharides - pharmacology Lymph Nodes - immunology Lymphocytes Lymphocytes T Male Matrix metalloproteinase Medical research Mice Mice, Inbred DBA Mice, Knockout Polymerase chain reaction Rheumatoid arthritis RNA, Messenger - biosynthesis RNA, Messenger - genetics Signal transduction Signal Transduction - immunology Spleen Spleen - immunology Suppressor of Cytokine Signaling 3 Protein - biosynthesis Suppressor of Cytokine Signaling 3 Protein - genetics Suppressor of Cytokine Signaling 3 Protein - immunology Synovitis Tumor necrosis factor Tumor necrosis factor-TNF γ-Interferon |
| title | Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis |
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