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IL-6 amplifies TLR mediated cytokine and chemokine production: implications for the pathogenesis of rheumatic inflammatory diseases
The role of Interleukin(IL)-6 in the pathogenesis of joint and systemic inflammation in rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis (s-JIA) has been clearly demonstrated. However, the mechanisms by which IL-6 contributes to the pathogenesis are not completely understood. Thi...
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| Published in: | PloS one 2014-10, Vol.9 (10), p.e107886-e107886 |
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| description | The role of Interleukin(IL)-6 in the pathogenesis of joint and systemic inflammation in rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis (s-JIA) has been clearly demonstrated. However, the mechanisms by which IL-6 contributes to the pathogenesis are not completely understood. This study investigates whether IL-6 affects, alone or upon toll like receptor (TLR) ligand stimulation, the production of inflammatory cytokines and chemokines in human peripheral blood mononuclear cells (PBMCs), synovial fluid mononuclear cells from JIA patients (SFMCs) and fibroblast-like synoviocytes from rheumatoid arthritis patients (RA synoviocytes) and signalling pathways involved. PBMCs were pre-treated with IL-6 and soluble IL-6 Receptor (sIL-6R). SFMCs and RA synoviocytes were pre-treated with IL-6/sIL-6R or sIL-6R, alone or in combination with Tocilizumab (TCZ). Cells were stimulated with LPS, S100A8-9, poly(I-C), CpG, Pam2CSK4, MDP, IL-1β. Treatment of PBMCs with IL-6 induced production of TNF-α, CXCL8, and CCL2, but not IL-1β. Addition of IL-6 to the same cells after stimulation with poly(I-C), CpG, Pam2CSK4, and MDP induced a significant increase in IL-1β and CXCL8, but not TNF-α production compared with TLR ligands alone. This enhanced production of IL-1β and CXCL8 paralleled increased p65 NF-κB activation. In contrast, addition of IL-6 to PBMCs stimulated with LPS or S100A8-9 (TLR-4 ligands) led to reduction of IL-1β, TNF-α and CXCL8 with reduced p65 NF-κB activation. IL-6/IL-1β co-stimulation increased CXCL8, CCL2 and IL-6 production. Addition of IL-6 to SFMCs stimulated with LPS or S100A8 increased CXCL8, CCL2 and IL-1β production. Treatment of RA synoviocytes with sIL-6R increased IL-6, CXCL8 and CCL2 production, with increased STAT3 and p65 NF-κB phosphorylation. Our results suggest that IL-6 amplifies TLR-induced inflammatory response. This effect may be relevant in the presence of high IL-6 and sIL-6R levels, such as in arthritic joints in the context of stimulation by endogenous TLR ligands. |
| doi_str_mv | 10.1371/journal.pone.0107886 |
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However, the mechanisms by which IL-6 contributes to the pathogenesis are not completely understood. This study investigates whether IL-6 affects, alone or upon toll like receptor (TLR) ligand stimulation, the production of inflammatory cytokines and chemokines in human peripheral blood mononuclear cells (PBMCs), synovial fluid mononuclear cells from JIA patients (SFMCs) and fibroblast-like synoviocytes from rheumatoid arthritis patients (RA synoviocytes) and signalling pathways involved. PBMCs were pre-treated with IL-6 and soluble IL-6 Receptor (sIL-6R). SFMCs and RA synoviocytes were pre-treated with IL-6/sIL-6R or sIL-6R, alone or in combination with Tocilizumab (TCZ). Cells were stimulated with LPS, S100A8-9, poly(I-C), CpG, Pam2CSK4, MDP, IL-1β. Treatment of PBMCs with IL-6 induced production of TNF-α, CXCL8, and CCL2, but not IL-1β. Addition of IL-6 to the same cells after stimulation with poly(I-C), CpG, Pam2CSK4, and MDP induced a significant increase in IL-1β and CXCL8, but not TNF-α production compared with TLR ligands alone. This enhanced production of IL-1β and CXCL8 paralleled increased p65 NF-κB activation. In contrast, addition of IL-6 to PBMCs stimulated with LPS or S100A8-9 (TLR-4 ligands) led to reduction of IL-1β, TNF-α and CXCL8 with reduced p65 NF-κB activation. IL-6/IL-1β co-stimulation increased CXCL8, CCL2 and IL-6 production. Addition of IL-6 to SFMCs stimulated with LPS or S100A8 increased CXCL8, CCL2 and IL-1β production. Treatment of RA synoviocytes with sIL-6R increased IL-6, CXCL8 and CCL2 production, with increased STAT3 and p65 NF-κB phosphorylation. Our results suggest that IL-6 amplifies TLR-induced inflammatory response. This effect may be relevant in the presence of high IL-6 and sIL-6R levels, such as in arthritic joints in the context of stimulation by endogenous TLR ligands.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0107886</identifier><identifier>PMID: 25271853</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Arthritis ; Biology and life sciences ; Chemokines ; Chemokines - biosynthesis ; Cytokines ; Cytokines - biosynthesis ; Families & family life ; Fibroblasts ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Fluids ; Humans ; Immunoglobulins ; Immunology ; Inflammation ; Inflammation Mediators - metabolism ; Inflammatory diseases ; Inflammatory response ; Interleukin 6 ; Interleukin 6 receptors ; Interleukin-6 - metabolism ; Interleukin-6 - pharmacology ; Joint diseases ; Kinases ; Leukocytes (mononuclear) ; Leukocytes, Mononuclear - drug effects ; Leukocytes, Mononuclear - metabolism ; Ligands ; Lipopolysaccharides ; Lymphocytes ; Medicine and Health Sciences ; Monocyte chemoattractant protein 1 ; NF-κB protein ; Pathogenesis ; Patients ; Peripheral blood mononuclear cells ; Phosphorylation ; Rheumatic Diseases - metabolism ; Rheumatoid arthritis ; Rheumatology ; Signal Transduction ; Signaling ; Stat3 protein ; Stimulation ; Synovial fluid ; Synovial Membrane - metabolism ; Synoviocytes ; Toll-like receptors ; Toll-Like Receptors - metabolism ; Tumor necrosis factor-α</subject><ispartof>PloS one, 2014-10, Vol.9 (10), p.e107886-e107886</ispartof><rights>2014 Caiello 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>2014 Caiello et al 2014 Caiello et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-136c7b69212ed56cb5b2ae7c3a06df0bdbdbdcf8a9b75936dd10c30a8336383e3</citedby><cites>FETCH-LOGICAL-c526t-136c7b69212ed56cb5b2ae7c3a06df0bdbdbdcf8a9b75936dd10c30a8336383e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1566821965/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1566821965?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,25783,27957,27958,37047,37048,44625,53827,53829,75483</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25271853$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Lin, Wenyu</contributor><creatorcontrib>Caiello, Ivan</creatorcontrib><creatorcontrib>Minnone, Gaetana</creatorcontrib><creatorcontrib>Holzinger, Dirk</creatorcontrib><creatorcontrib>Vogl, Thomas</creatorcontrib><creatorcontrib>Prencipe, Giusi</creatorcontrib><creatorcontrib>Manzo, Antonio</creatorcontrib><creatorcontrib>De Benedetti, Fabrizio</creatorcontrib><creatorcontrib>Strippoli, Raffaele</creatorcontrib><title>IL-6 amplifies TLR mediated cytokine and chemokine production: implications for the pathogenesis of rheumatic inflammatory diseases</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The role of Interleukin(IL)-6 in the pathogenesis of joint and systemic inflammation in rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis (s-JIA) has been clearly demonstrated. However, the mechanisms by which IL-6 contributes to the pathogenesis are not completely understood. This study investigates whether IL-6 affects, alone or upon toll like receptor (TLR) ligand stimulation, the production of inflammatory cytokines and chemokines in human peripheral blood mononuclear cells (PBMCs), synovial fluid mononuclear cells from JIA patients (SFMCs) and fibroblast-like synoviocytes from rheumatoid arthritis patients (RA synoviocytes) and signalling pathways involved. PBMCs were pre-treated with IL-6 and soluble IL-6 Receptor (sIL-6R). SFMCs and RA synoviocytes were pre-treated with IL-6/sIL-6R or sIL-6R, alone or in combination with Tocilizumab (TCZ). Cells were stimulated with LPS, S100A8-9, poly(I-C), CpG, Pam2CSK4, MDP, IL-1β. Treatment of PBMCs with IL-6 induced production of TNF-α, CXCL8, and CCL2, but not IL-1β. Addition of IL-6 to the same cells after stimulation with poly(I-C), CpG, Pam2CSK4, and MDP induced a significant increase in IL-1β and CXCL8, but not TNF-α production compared with TLR ligands alone. This enhanced production of IL-1β and CXCL8 paralleled increased p65 NF-κB activation. In contrast, addition of IL-6 to PBMCs stimulated with LPS or S100A8-9 (TLR-4 ligands) led to reduction of IL-1β, TNF-α and CXCL8 with reduced p65 NF-κB activation. IL-6/IL-1β co-stimulation increased CXCL8, CCL2 and IL-6 production. Addition of IL-6 to SFMCs stimulated with LPS or S100A8 increased CXCL8, CCL2 and IL-1β production. Treatment of RA synoviocytes with sIL-6R increased IL-6, CXCL8 and CCL2 production, with increased STAT3 and p65 NF-κB phosphorylation. Our results suggest that IL-6 amplifies TLR-induced inflammatory response. This effect may be relevant in the presence of high IL-6 and sIL-6R levels, such as in arthritic joints in the context of stimulation by endogenous TLR ligands.</description><subject>Activation</subject><subject>Arthritis</subject><subject>Biology and life sciences</subject><subject>Chemokines</subject><subject>Chemokines - biosynthesis</subject><subject>Cytokines</subject><subject>Cytokines - biosynthesis</subject><subject>Families & family life</subject><subject>Fibroblasts</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Fluids</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Immunology</subject><subject>Inflammation</subject><subject>Inflammation Mediators - metabolism</subject><subject>Inflammatory diseases</subject><subject>Inflammatory response</subject><subject>Interleukin 6</subject><subject>Interleukin 6 receptors</subject><subject>Interleukin-6 - metabolism</subject><subject>Interleukin-6 - pharmacology</subject><subject>Joint diseases</subject><subject>Kinases</subject><subject>Leukocytes (mononuclear)</subject><subject>Leukocytes, Mononuclear - drug effects</subject><subject>Leukocytes, Mononuclear - metabolism</subject><subject>Ligands</subject><subject>Lipopolysaccharides</subject><subject>Lymphocytes</subject><subject>Medicine and Health Sciences</subject><subject>Monocyte chemoattractant protein 1</subject><subject>NF-κB protein</subject><subject>Pathogenesis</subject><subject>Patients</subject><subject>Peripheral blood mononuclear cells</subject><subject>Phosphorylation</subject><subject>Rheumatic Diseases - metabolism</subject><subject>Rheumatoid arthritis</subject><subject>Rheumatology</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Stat3 protein</subject><subject>Stimulation</subject><subject>Synovial fluid</subject><subject>Synovial Membrane - metabolism</subject><subject>Synoviocytes</subject><subject>Toll-like receptors</subject><subject>Toll-Like Receptors - 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metabolism</topic><topic>Rheumatoid arthritis</topic><topic>Rheumatology</topic><topic>Signal Transduction</topic><topic>Signaling</topic><topic>Stat3 protein</topic><topic>Stimulation</topic><topic>Synovial fluid</topic><topic>Synovial Membrane - metabolism</topic><topic>Synoviocytes</topic><topic>Toll-like receptors</topic><topic>Toll-Like Receptors - metabolism</topic><topic>Tumor necrosis factor-α</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Caiello, Ivan</creatorcontrib><creatorcontrib>Minnone, Gaetana</creatorcontrib><creatorcontrib>Holzinger, Dirk</creatorcontrib><creatorcontrib>Vogl, Thomas</creatorcontrib><creatorcontrib>Prencipe, Giusi</creatorcontrib><creatorcontrib>Manzo, Antonio</creatorcontrib><creatorcontrib>De Benedetti, Fabrizio</creatorcontrib><creatorcontrib>Strippoli, Raffaele</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 Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>ProQuest_Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database (ProQuest Medical & Health Databases)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Database (1962 - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Caiello, Ivan</au><au>Minnone, Gaetana</au><au>Holzinger, Dirk</au><au>Vogl, Thomas</au><au>Prencipe, Giusi</au><au>Manzo, Antonio</au><au>De Benedetti, Fabrizio</au><au>Strippoli, Raffaele</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>IL-6 amplifies TLR mediated cytokine and chemokine production: implications for the pathogenesis of rheumatic inflammatory diseases</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-10-01</date><risdate>2014</risdate><volume>9</volume><issue>10</issue><spage>e107886</spage><epage>e107886</epage><pages>e107886-e107886</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Conceived and designed the experiments: IC GP FD RS. Performed the experiments: IC DH GM RS. Analyzed the data: IC DH GP TV FDB RS. Contributed reagents/materials/analysis tools: DH TV AM FDB. Contributed to the writing of the manuscript: DH GP FDB RS.</notes><notes>Competing Interests: Dr De Benedetti’s Institution received unrestricted research grants from Pfizer, Abbvie, Novartis, Novimmune, Roche, SOBI and travel support from Roche. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. The other authors declare that they have no competing interests.</notes><abstract>The role of Interleukin(IL)-6 in the pathogenesis of joint and systemic inflammation in rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis (s-JIA) has been clearly demonstrated. However, the mechanisms by which IL-6 contributes to the pathogenesis are not completely understood. This study investigates whether IL-6 affects, alone or upon toll like receptor (TLR) ligand stimulation, the production of inflammatory cytokines and chemokines in human peripheral blood mononuclear cells (PBMCs), synovial fluid mononuclear cells from JIA patients (SFMCs) and fibroblast-like synoviocytes from rheumatoid arthritis patients (RA synoviocytes) and signalling pathways involved. PBMCs were pre-treated with IL-6 and soluble IL-6 Receptor (sIL-6R). SFMCs and RA synoviocytes were pre-treated with IL-6/sIL-6R or sIL-6R, alone or in combination with Tocilizumab (TCZ). Cells were stimulated with LPS, S100A8-9, poly(I-C), CpG, Pam2CSK4, MDP, IL-1β. Treatment of PBMCs with IL-6 induced production of TNF-α, CXCL8, and CCL2, but not IL-1β. Addition of IL-6 to the same cells after stimulation with poly(I-C), CpG, Pam2CSK4, and MDP induced a significant increase in IL-1β and CXCL8, but not TNF-α production compared with TLR ligands alone. This enhanced production of IL-1β and CXCL8 paralleled increased p65 NF-κB activation. In contrast, addition of IL-6 to PBMCs stimulated with LPS or S100A8-9 (TLR-4 ligands) led to reduction of IL-1β, TNF-α and CXCL8 with reduced p65 NF-κB activation. IL-6/IL-1β co-stimulation increased CXCL8, CCL2 and IL-6 production. Addition of IL-6 to SFMCs stimulated with LPS or S100A8 increased CXCL8, CCL2 and IL-1β production. Treatment of RA synoviocytes with sIL-6R increased IL-6, CXCL8 and CCL2 production, with increased STAT3 and p65 NF-κB phosphorylation. Our results suggest that IL-6 amplifies TLR-induced inflammatory response. This effect may be relevant in the presence of high IL-6 and sIL-6R levels, such as in arthritic joints in the context of stimulation by endogenous TLR ligands.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25271853</pmid><doi>10.1371/journal.pone.0107886</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-10, Vol.9 (10), p.e107886-e107886 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1566821965 |
| source | Publicly Available Content Database; PubMed Central |
| subjects | Activation Arthritis Biology and life sciences Chemokines Chemokines - biosynthesis Cytokines Cytokines - biosynthesis Families & family life Fibroblasts Fibroblasts - drug effects Fibroblasts - metabolism Fluids Humans Immunoglobulins Immunology Inflammation Inflammation Mediators - metabolism Inflammatory diseases Inflammatory response Interleukin 6 Interleukin 6 receptors Interleukin-6 - metabolism Interleukin-6 - pharmacology Joint diseases Kinases Leukocytes (mononuclear) Leukocytes, Mononuclear - drug effects Leukocytes, Mononuclear - metabolism Ligands Lipopolysaccharides Lymphocytes Medicine and Health Sciences Monocyte chemoattractant protein 1 NF-κB protein Pathogenesis Patients Peripheral blood mononuclear cells Phosphorylation Rheumatic Diseases - metabolism Rheumatoid arthritis Rheumatology Signal Transduction Signaling Stat3 protein Stimulation Synovial fluid Synovial Membrane - metabolism Synoviocytes Toll-like receptors Toll-Like Receptors - metabolism Tumor necrosis factor-α |
| title | IL-6 amplifies TLR mediated cytokine and chemokine production: implications for the pathogenesis of rheumatic inflammatory diseases |
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