Toll-like receptor 2 ligand mediates the upregulation of angiogenic factor, vascular endothelial growth factor and interleukin-8/CXCL8 in human rheumatoid synovial fibroblasts

Cho, Mi‐La; Ju, Ji-hyun; Kim, Hae-Rim; Oh, Hyeyoung; Kang, Chang-Suk; Jhun, JooYeon; Lee, Seon‐Yeong; Park, Mi-Kyung; Min, Jun‐Ki; Park, Sung-Hwan; Lee, Sang‐Heon; Kim, Ho-Youn

doi:10.1016/j.imlet.2006.11.005

Cited by 86 publications

(48 citation statements)

References 33 publications

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“…38 TNF-a or IL-1b can potently induce the expression of CXCL8 in cultured FLS. 39 We found that monosodium urate crystals exhibited synergistic effects with TNF-a or IL-1b to induce CXCL8 release from normal FLS. Since FLS, neutrophils and mononuclear cells play important roles in the pathogenesis of arthritis, the enhanced production of the chemokine CXCL8 can attract mononuclear cells and neutrophils towards FLS downstream of monosodium urate crystals, TNF-a and IL-1b together to contribute to the development of inflammation.…”

Section: Discussionmentioning

confidence: 73%

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

et al. 2011

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Hyperuricemia-mediated uric acid crystal formation may cause joint inflammation and provoke the destruction of joints through the activation of inflammasome-mediated innate immune responses. However, the immunopathological effects and underlying intracellular regulatory mechanisms of uric acid crystal-mediated activation of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) have not been elucidated. Therefore, we investigated the in vitro effects of monosodium urate crystals, alone or in combination with the inflammatory cytokines tumor-necrosis factor (TNF)-a or interleukin (IL)-1b, on the activation of human FLS from RA patients and normal control subjects and the underlying intracellular signaling mechanisms of treatment with these crystals. Monosodium urate crystals were able to significantly increase the release of the inflammatory cytokine IL-6, the chemokine CXCL8 and the matrix metalloproteinase (MMP)-1 from both normal and RA-FLS (all P,0.05). Moreover, the additive or synergistic effect on the release of IL-6, CXCL8 and MMP-1 from both normal and RA-FLS was observed following the combined treatment with monosodium urate crystals and TNF-a or IL-1b. Further experiments showed that the release of the measured inflammatory cytokine, chemokine and MMP-1 stimulated by monosodium urate crystals were differentially regulated by the intracellular activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase pathways but not the p38 mitogen-activated protein kinase pathway. Our results therefore provide a new insight into the uric acid crystal-activated immunopathological mechanisms mediated by distinct intracellular signal transduction pathways leading to joint inflammation in RA. Keywords: cytokines; fibroblast-like synoviocytes; rheumatoid arthritis; signal transduction; uric acid INTRODUCTION Arthritis is the most common cause of joint pain and physical disability in developed countries and worldwide. 1 Gout is an acute inflammatory arthritis whose incidence has increased over the past decade, which is characterized by elevated serum urate concentrations and recurrent attacks by intra-articular uric acid crystal deposition. 2 Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis with 1% prevalence in industrialized countries, which is characterized by cytokinemediated inflammation of the synovium and destruction of cartilage and bone. 3 Uric acid crystal-mediated gouty attacks have also been observed in patients with RA. 4,5 Fibroblast-like synoviocytes (FLS) are resident mesenchymal cells in synovial joints that play crucial roles in both joint damage and the propagation of inflammation in arthritic diseases. 6 The ability of FLS to erode cartilage is a multistep process that includes the attachment of FLS onto cartilage and the synthesis of matrix metalloproteinases (MMPs) such as MMP-1. 7 Additionally, FLS secrete receptor activator of nuclear factor-kB ligand, which can attract macrophages from the vasculature, stimulate the differentiation of vascular-and tiss...

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Section: Discussionmentioning

confidence: 73%

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

et al. 2011

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“…Vascular endothelial growth factor A, interleukin 8, and chemokine (C-C motif) ligand 5 are among the inflammatory cytokines/chemokines associated with stroma-like activities (Shono et al, 1996;Moriuchi et al, 1997;Yoshida et al, 1997;Cho et al, 2007). Among the highly ranked genes, we also noticed Toll-like receptor 1, another upstream activator for NF-kB, and stromal cell-derived factor 2-like 1, which is reported to be upregulated through EMT, an important biological output of the TGF-b pathway (Massagué, 2008;Sarrio et al, 2008;Rakoff-Nahoum and Medzhitov, 2009).…”

Section: Btmentioning

confidence: 99%

Gene set enrichment analysis provides insight into novel signalling pathways in breast cancer stem cells

et al. 2009

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BACKGROUND: Tumour-initiating cells (TICs) or cancer stem cells can exist as a small population in malignant tissues. The signalling pathways activated in TICs that contribute to tumourigenesis are not fully understood. METHODS: Several breast cancer cell lines were sorted with CD24 and CD44, known markers for enrichment of breast cancer TICs. Tumourigenesis was analysed using sorted cells and total RNA was subjected to gene expression profiling and gene set enrichment analysis (GSEA). RESULTS: We showed that several breast cancer cell lines have a small population of CD24 À/low /CD44 þ cells in which TICs may be enriched, and confirmed the properties of TICs in a xenograft model. GSEA revealed that CD24 À/low /CD44 þ cell populations are enriched for genes involved in transforming growth factor-b, tumour necrosis factor, and interferon response pathways. Moreover, we found the presence of nuclear factor-kB (NF-kB) activity in CD24 À/low /CD44 þ cells, which was previously unrecognised. In addition, NF-kB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) prevented tumourigenesis of CD24 À/low / CD44 þ cells in vivo. CONCLUSION: Our findings suggest that signalling pathways identified using GSEA help to identify molecular targets and biomarkers for TIC-like cells.

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“…CXCL12 was increased in JIA FLS, but is reportedly decreased in RA synovial tissue 23, suggesting differences in pathways utilized for cell trafficking. CXCL8 has been observed in RA synovial tissue 23, but specifically in many cell types from the RA joint, including dendritic cells, synovial macrophages, neutrophils, and synovial fibroblasts 23, 24, 25, 26, 27, 28, in addition to synovial fluid of JIA 21, but had the largest fold‐change decrease in expression in cultured JIA FLS. When tested on synovial fluid there was no significant difference in expression, suggesting that there are likely other cell sources of CXCL8 in JIA as well.…”

Section: Resultsmentioning

confidence: 99%

Secretion of pro‐inflammatory cytokines and chemokines and loss of regulatory signals by fibroblast‐like synoviocytes in juvenile idiopathic arthritis

Brescia

Simonds

Sullivan

et al. 2017

Proteomics Clinical Apps

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PurposeThe goal is to investigate the specific contribution of fibroblast‐like synoviocytes (FLS) to the inflammatory milieu of the synovium in juvenile idiopathic arthritis (JIA) through detection of secreted proteins.Experimental designExpression of 89 cytokines and chemokines is determined on unprocessed synovial fluid from controls and JIA patients using antibody arrays. Supernatants from pure cell cultures of FLS grown from synovial fluids or tissues from JIA and controls are also examined for protein expression. Ingenuity Pathway Analysis (IPA) is revealed top pathways and upstream regulators of significant proteins.ResultsProtein studies is revealed that JIA FLS release pro‐inflammatory cytokines and chemokines, including IL‐4, IL‐6, IL‐17, CXCL1, and CXCL6, and lose expression of important regulator signals, such as IL‐10 and TIMP2. Of the 84 proteins differentially expressed between controls and JIA in the synovial fluid, 1/3 (29 proteins) are differentially expressed in the cell culture supernatants of JIA and control FLS. ELISA of cell culture supernatants and synovial fluid confirmed seven key proteins.Conclusion and clinical relevanceJIA FLS are central to perpetuation of inflammation in JIA, including trafficking of inflammatory cells and effects on the extracellular matrix. These cells express key disease‐specific chemokines that, with further refinement, may allow us to tailor therapy appropriately.

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Toll-like receptor 2 ligand mediates the upregulation of angiogenic factor, vascular endothelial growth factor and interleukin-8/CXCL8 in human rheumatoid synovial fibroblasts

Cited by 86 publications

References 33 publications

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

Gene set enrichment analysis provides insight into novel signalling pathways in breast cancer stem cells

Secretion of pro‐inflammatory cytokines and chemokines and loss of regulatory signals by fibroblast‐like synoviocytes in juvenile idiopathic arthritis

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