RNA sensors in human osteoarthritis and rheumatoid arthritis synovial fibroblasts: Immune regulation by vasoactive intestinal peptide

Carrión, Mar; Juarranz, Yasmina; Pérez‐García, Selene; Jimeno, Rebeca; Pablos, José L.; Gomariz, Rosa P.; Gutiérrez‐Cañas, Irene

doi:10.1002/art.30294

Cited by 61 publications

(56 citation statements)

References 52 publications

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“…Considering that VIP alters the expression and function of TLR3 and TLR4 in FLS [17,23], we further studied its effect on IL-17R combined with these treatments. In this case, VIP is able to lessen the poly(I:C)-induced expression of IL-17RA in RA-FLS (fig.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously described that TLR3 engagement by poly(I:C) induces nuclear translocation of NF-κB and AP-1 in FLS. NF-κB activation was significantly stronger in RA-FLS than in OA-FLS [23], supporting upregulation of IL-17RA expression in RA-FLS. Regarding IL-17RC mRNA induction by poly(I:C), enhanced expression was observed in both OA-FLS and RA-FLS, being in agreement with the similar activation of AP-1 induced by poly(I:C) in both types of FLS [23].…”

Section: Discussionmentioning

confidence: 99%

“…NF-κB activation was significantly stronger in RA-FLS than in OA-FLS [23], supporting upregulation of IL-17RA expression in RA-FLS. Regarding IL-17RC mRNA induction by poly(I:C), enhanced expression was observed in both OA-FLS and RA-FLS, being in agreement with the similar activation of AP-1 induced by poly(I:C) in both types of FLS [23]. TLR4 expression is increased in RA-FLS compared with OA-FLS [17] possibly explaining the LPS induction of IL-17RA restricted to RA-FLS.…”

Section: Discussionmentioning

confidence: 99%

“…As IL-6 is involved in Th17 differentiation, VIP inhibition of this cytokine could represent an additional checkpoint in this pathology. Moreover, data from our laboratory have reported that VIP reduced interferon β production after TLR3 engagement in FLS [23], which may explain the inhibitory effect of VIP on IL-12 and IL-23 in FLS after treatment with TNFα, LPS and poly(I:C). The capacity of VIP to counteract the enhancing effect of proinflammatory molecules on IL-17R and the IL-12 family of cytokines corroborates and amplifies the beneficial effect of this endogenous peptide in rheumatic diseases and confirms that it is able to interfere with TNFα signaling [17,23].…”

Section: Discussionmentioning

confidence: 99%

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Inflammatory Mediators Alter Interleukin-17 Receptor, Interleukin-12 and -23 Expression in Human Osteoarthritic and Rheumatoid Arthritis Synovial Fibroblasts: Immunomodulation by Vasoactive Intestinal Peptide

Carrión

Pérez‐García

Jimeno

et al. 2013

Neuroimmunomodulation

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Aims: To assess the contribution of fibroblast-like synoviocytes (FLS) to the inflammatory joint microenvironment under different pathogenic stimuli and their potential to respond to interleukin (IL)-17 and to determine whether the neuroimmunomodulatory vasoactive intestinal peptide (VIP) is able to modulate IL-17 receptor (IL-17R) and related cytokines. Methods: The effect of proinflammatory cytokines [tumor necrosis factor α (TNFα) and IL-17] and Toll-like receptor (TLR) ligands [poly(I:C) and lipopolysaccharide (LPS)] on IL-17R expression and IL-12 and IL-23 production was studied in osteoarthritis (OA)- and rheumatoid arthritis (RA)-FLS, involved in Th1/Th17 differentiation. The effect of VIP was also determined. IL-17RA, IL-17RC, IL-12p35 and IL-23p19 expression was measured by real-time polymerase chain reaction. IL-12 and IL-23 protein levels were measured by ELISA in supernatant cultures. Results: TNFα, LPS and poly(I:C) induced an increase in IL-17RA in RA-FLS, whereas TNFα, TNFα plus IL-17 and poly(I:C) enhanced IL-17RC transcripts in FLS. VIP diminished the upregulated expression of IL-17RA in RA-FLS following TNFα and poly(I:C). TNFα, LPS and poly(I:C) increased IL-12 and IL-23 levels in cells derived from patients presenting both pathologies. However, IL-17A decreased IL-12 and augmented IL-23. VIP decreased IL-12p35 mRNA upregulation by poly(I:C) and IL-23p19 transcripts in LPS-treated FLS. Conclusions: Inflammatory cytokines and TLR ligands modulate IL-17R, IL-12 and IL-23 possibly favoring the cross talk between FLS and Th1/Th17 cells. The ability of VIP to counteract the enhancing effect of proinflammatory molecules on IL-17R and the IL-12 family of cytokines corroborates and amplifies the beneficial effect of this endogenous neuroimmunopeptide in rheumatic diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Inflammatory Mediators Alter Interleukin-17 Receptor, Interleukin-12 and -23 Expression in Human Osteoarthritic and Rheumatoid Arthritis Synovial Fibroblasts: Immunomodulation by Vasoactive Intestinal Peptide

Carrión

Pérez‐García

Jimeno

et al. 2013

Neuroimmunomodulation

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“…Notably, TLR, cytosolic DNA-sensing, and NOD-like receptor pathways are significantly enriched in the KEGG analysis for differentially methylated genes. Each pathway has been implicated as fundamental mechanisms that regulate the inflammatory response in RA [24][25][26]. Genes regulating innate immunity are emerging as potential therapeutic targets for RA, and the methylation data supports their participation in The data suggest that pathway analysis can provide other clues for disease pathogenesis and novel therapeutic interventions.…”

Section: Discussionmentioning

confidence: 88%

Genome Wide Association Study to Predict Severe Asthma Exacerbations in Children Using Random Forests Classifi ers

Ayyanathan¹

2014

Specific Gene Expression and Epigenetics

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Background: A DNA methylation signature has been characterized that distinguishes rheumatoid arthritis (RA) fibroblast like synoviocytes (FLS) from osteoarthritis (OA) FLS. The presence of epigenetic changes in long-term cultured cells suggest that rheumatoid FLS imprinting might contribute to pathogenic behavior. To understand how differentially methylated genes (DMGs) might participate in the pathogenesis of RA, we evaluated the stability of the RA signature and whether DMGs are enriched in specific pathways and ontology categories. Methods: To assess the RA methylation signatures the Illumina HumanMethylation450 chip was used to compare methylation levels in RA, OA, and normal (NL) FLS at passage 3, 5, and 7. Then methylation frequencies at CpGs within the signature were compared between passages. To assess the enrichment of DMGs in specific pathways, DMGs were identified as genes that possess significantly differential methylated loci within their promoter regions. These sets of DMGs were then compared to pathway and ontology databases to establish enrichment in specific categories. Results: Initial studies compared passage 3, 5, and 7 FLS from RA, OA, and NL. The patterns of differential methylation of each individual FLS line were very similar regardless of passage number. Using the most robust analysis, 20 out of 272 KEGG pathways and 43 out of 34,400 GO pathways were significantly altered for RA compared with OA and NL FLS. Most interestingly, we found that the KEGG 'Rheumatoid Arthritis' pathway was consistently the most significantly enriched with differentially methylated loci. Additional pathways involved with innate immunity (Complement and Coagulation, Toll-like Receptors, NOD-like Receptors, and Cytosolic DNAsensing), cell adhesion (Focal Adhesion, Cell Adhesion Molecule), and cytokines (Cytokine-cytokine Receptor). Taken together, KEGG and GO pathway analysis demonstrates non-random epigenetic imprinting of RA FLS. Conclusions: The DNA methylation patterns include anomalies in key genes implicated in the pathogenesis of RA and are stable for multiple cell passages. Persistent epigenetic alterations could contribute to the aggressive phenotype of RA synoviocytes and identify potential therapeutic targets that could modulate the pathogenic behavior.

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Matrix Metalloproteinase 13 Expression in Response to Double‐Stranded RNA in Human Chondrocytes

Radwan¹,

Gavriilidis²,

Robinson³

et al. 2013

Arthritis & Rheumatism

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Objective. To investigate the mechanism of matrix metalloproteinase 13 (MMP-13) expression in chondrocytes via pattern-recognition receptors (PRRs) for double-stranded RNA (dsRNA). Conclusion. Signaling by dsRNA in chondrocytes requires a range of PRRs, including TLR-3, RIG-1, and MDA-5, for the full-induction of MMP13, thus providing tight regulation of a gene critical for maintenance of cartilage integrity. Our data add to the understanding of MMP13 regulation, which is essential before such mechanisms can be exploited to alleviate the cartilage destruction associated with OA. Methods. Differential expression of PRRs was

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RNA sensors in human osteoarthritis and rheumatoid arthritis synovial fibroblasts: Immune regulation by vasoactive intestinal peptide

Cited by 61 publications

References 52 publications

Inflammatory Mediators Alter Interleukin-17 Receptor, Interleukin-12 and -23 Expression in Human Osteoarthritic and Rheumatoid Arthritis Synovial Fibroblasts: Immunomodulation by Vasoactive Intestinal Peptide

Inflammatory Mediators Alter Interleukin-17 Receptor, Interleukin-12 and -23 Expression in Human Osteoarthritic and Rheumatoid Arthritis Synovial Fibroblasts: Immunomodulation by Vasoactive Intestinal Peptide

Genome Wide Association Study to Predict Severe Asthma Exacerbations in Children Using Random Forests Classifi ers

Matrix Metalloproteinase 13 Expression in Response to Double‐Stranded RNA in Human Chondrocytes

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