Dehydroevodiamine Suppresses Inflammatory Responses in Adjuvant-Induced Arthritis Rats and Human Fibroblast-Like Synoviocytes

AbstractC-X-C motif chemokine 10 (CXCL10) is an inflammatory chemokine and a key molecule in the pathogenesis of rheumatoid arthritis (RA). Melanoma differentiation-associated gene 5 (MDA5) is an RNA helicase that plays a role in innate immune and inflammatory reactions. The details of the regulatory mechanisms of CXCL10 production and the precise role of MDA5 in RA synovitis have not been fully elucidated. The aim of this study was to examine the role of MDA5 in regulating CXCL10 expression in cultured human rheumatoid fibroblast-like synoviocytes (RFLS). RFLS was stimulated with Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA mimetic. Expression of interferon beta (IFN-β), MDA5, and CXCL10 was measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay. A neutralizing antibody of IFN-β and siRNA-mediated MDA5 knockdown were used to determine the role of these molecules in regulating CXCL10 expression downstream of TLR3 signaling in RFLS. Poly I:C induced IFN-β, MDA5, and CXCL10 expression in a concentration- and time-dependent manner. IFN-β neutralizing antibody suppressed the expression of MDA5 and CXCL10, and knockdown of MDA5 decreased a part of CXCL10 expression (p < 0.001). The TLR3/IFN-β/CXCL10 axis may play a crucial role in the inflammatory responses in RA synovium, and MDA5 may be partially involved in this axis.

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SAT0007 BLOCKING HISTAMINE-RELEASING FACTOR/TRANSLATIONALLY CONTROLLED TUMOR PROTEIN (HRF/TCTP) ATTENUATES AGGRESSIVENESS OF FIBROBLAST-LIKE SYNOVIOCYTES AND AMELIORATES COLLAGEN-INDUCED ARTHRITIS IN RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5088 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 934.3-934

Author(s):

M. Kim ◽

Y. Choe ◽

H. Lee ◽

Y. H. Cheon ◽

S. I. Lee

Keyword(s):

Rheumatoid Arthritis ◽

Cancer Progression ◽

Inflammatory Responses ◽

Joint Destruction ◽

Serum Levels ◽

Therapeutic Effects ◽

Collagen Induced Arthritis ◽

Translationally Controlled Tumor Protein ◽

Biochemical Analyses ◽

Fibroblast Like Synoviocytes

Background:Histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses. Increased expression of HRF/TCTP occurs in joints of rheumatoid arthritis (RA) patients, but the role of HRF/TCTP in RA remains undefinedObjectives:In this study, we explored the pathogenic significance of HRF/TCTP and evaluated therapeutic effects of HRF/TCTP blockade in RA.Methods:HRF/TCTP transgenic (TG) and knockdown (KD) mice with collagen-induced arthritis (CIA) were used to determine experimental phenotypes of RA. HRF/TCTP levels were measured in sera and joint fluids in patients with RA and compared to those with osteoarthritis, ankylosing spondylitis, Behcet disease, and healthy controls. HRF/TCTP expression was also assessed in synovium and fibroblast-like synoviocytes (FLS) obtained from RA or OA patients. Finally, we assessed effects of HRF/TCTP and dimerized HRF/TCTP binding peptide-2 (dTBP2), an inhibitor of HRF/TCTP, in RA-FLS and CIA mice.Results:Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were increased in HRF/TCTP TG mice, and decreased in KD mice compared to wild-type littermates. HRF/TCTP levels were higher in sera, synovial fluid, synovium, and FLS of patients with RA than in control groups. Serum levels of HRF/TCTP correlated well with disease activity in RA. Tumor-like aggressiveness of RA-FLS was exacerbated by HRF/TCTP stimulation and ameliorated by dTBP2 treatment. dTBP2 exerted protective and therapeutic effects in CIA mice, and had no detrimental effect in a murine tuberculosis model.Conclusion:Our results indicate that HRF/TCTP represents a novel biomarker and therapeutic target for diagnosis and treatment of RA.References:N/AAcknowledgments :National Research Foundation of KoreaKorea Health Industry Development InstituteDisclosure of Interests:None declared

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