ZNRF3 Regulates Collagen-Induced Arthritis Through NF-kB and Wnt Pathways.

Although the E3 ubiquitin ligase Zinc and ring finger 3 (ZNRF3) negatively regulates the Wnt signaling pathway, its function in rheumatoid arthritis (RA) is elusive. Here, the effects and the mechanism of ZNRF3 on a mouse model of collagen-induced arthritis (CIA) and human fibroblast-like synoviocytes (FLS) obtained from RA patients were determined. Our results showed that ZNRF3 was highly expressed in tissues and FLSs compared to trauma patients. Lentivirus-mediated silencing of ZNRF3 induced apoptosis decreased cell viability and significantly attenuated inflammation in RA-FLSs via tumor necrosis-α (TNF-α). Additionally, silencing of ZNRF3 reduced knee joint damage and also decreased the level of TNF-α, IL-1ß, and IL-6 in the CIA mouse model. These effects were mediated by the crosstalk between Wnt and NF-κB pathways in RA-FLS.

Diallyl Trisulfide can induce fibroblast-like synovial apoptosis and has a therapeutic effect on collagen-induced arthritis in mice via blocking NF-κB and Wnt pathways.

BACKGROUND: Diallyl Trisulfide (DATS) is an organosulfur compound extracted from garlic bulb, and exerts cardioprotective, anti-inflammatory, antioxidant, antimicrobial and anticancer effects. But its role in the pathogenesis of rheumatoid arthritis (RA) is unknown. Here we explored the influence of DATS on human fibroblast-like synoviocytes (FLS) isolated from RA patients and a mouse model of collagen-induced arthritis (CIA) and the underlying mechanism. METHODS: RA-FLS were cultured and treated with different concentrations of DATS. The CCK8 assay was used to assess cell proliferation while cell apoptosis was detected by flow cytometry and western blot. The IL-8, IL-6 and IL-1ß levels were determined using RT-qPCR and ELISA assay. The expression of proteins of the NF-κB and Wnt pathways were measured using western blot. Furthermore, the effect of DATS was also explored in vivo using the collagen-induced arthritis mouse model. The Th17/Treg pattern obtain from cells of spleen of collagen-induced arthritis mouse model was detected by flow cytometry. RESULTS: Our results showed that DATS could decrease cell viability and introduce apoptosis in RA-FLS. Furthermore, DATS significantly attenuated the production of key inflammatory cytokines induced by RA-FLS cells following treatment with tumor necrosis α (TNF-α) at a concentration of 100 µM or higher. This was due to its inhibitory effect on the NF-κB and Wnt pathway signaling in RA-FLS. Additionally, DATS decreased the production of inflammatory cytokines and regulated the immune function by restoring the balance between Th17 and Treg in CIA mouse model. CONCLUSIONS: In conclusion, DATS may serve as a potential curative agent for RA.

Dishevelled2 promotes apoptosis and inhibits inflammatory cytokine secretion in rheumatoid arthritis fibroblast-like synoviocytes through crosstalk with the NF-κB pathway.

Dishevelled (Dvl) not only links the canonical Wnt and non-canonical Wnt pathways but can also crosstalk with other pathways. As there is no systematic study to date on Dvl in rheumatoid arthritis (RA), we explored the impact of Dvl2 on proliferation and inflammatory cytokine secretion in RA fibroblast-like synoviocytes (FLSs). Expression of Dvl2 in RA synovial tissue and RA-FLSs was measured. Dvl2 was overexpressed in collagen-induced arthritis rats and human RA-FLSs,. the apoptosis and secretion of inflammatory cytokines were observed. Genetic changes and corresponding mechanisms caused by overexpressing Dvl2 in RA-FLSs were assessed. Dvl2 was found to be overexpressed in RA synovial tissue and RA-FLSs. Overexpression of Dvl2 increased apoptosis and inhibited inflammatory cytokine secretion by RA-FLSs in vivo and in vitro, and Dvl2 inhibited expression of anti-apoptotic and inflammatory genes. One possible mechanism is that Dvl2 decreases the nuclear translocation of P65 and inhibits its ability to bind to the promoters of NF-κB target genes. Our findings reveal an underappreciated role of Dvl2 in regulating inflammation and RA-FLS apoptosis and provide insight into crosstalk between the Wnt and nuclear factor-κB (NF-κB) pathways.

Plasma Interleukin-37 Is Elevated in Patients with Rheumatoid Arthritis: Its Correlation with Disease Activity and Th1/Th2/Th17-Related Cytokines.

Interleukin- (IL-) 37 is a novel anti-inflammatory cytokine that suppresses immune response and inflammation. This study was performed to determine whether IL-37 was elevated in patients with rheumatoid arthritis (RA) and investigate the correlation between IL-37 level and disease activity and the concentration of Th1/Th2/Th17-related cytokines. Clinical parameters of disease activity, including the 28-joint disease activity score (DAS28) and C-reactive protein (CRP), were collected in 34 RA patients and 34 age- and sex-matched healthy controls. Plasma IL-37 was measured by ELISA. Plasma levels of TNF-α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, IFN-γ, MCP-1, and MIP-1ß were analyzed using the Bio-Plex suspension array system. It was found that IL-37 levels were elevated markedly in RA patients and almost undetectable in healthy controls. In addition, IL-37 levels in patients with active RA were significantly enhanced as compared with those in patients of remission. More importantly, IL-37 showed a significant correlation with disease activity (DAS28) and IL-4, IL-7, IL-10, IL-12, and IL-13 concentrations in RA patients. These findings suggest that IL-37 plays an important role in the pathogenesis of RA and may prove to be a potential biomarker of active RA.

Association of TNF-α polymorphism with prediction of response to TNF blockers in spondyloarthritis and inflammatory bowel disease: a meta-analysis.

AIM: To explore whether TNF-α promoter -308 A/G and -857 C/T polymorphisms have an association with responsiveness to TNF blockers in spondyloarthritis and inflammatory bowel disease. METHODS: A meta-analysis was performed. Pooled odds ratios (ORs) and 95% CIs were calculated. RESULTS: Six relevant studies with a total of 211 spondyloarthritis patients and 392 inflammatory bowel disease patients were included. The results showed that the common allele (G and C, respectively) showed a better responsiveness than the minor allele (A and T, respectively). The -308 G/G genotype (OR: 2.31; 95% CI: 1.36-3.91; p = 0.002) and -857 C/C genotype (OR: 3.66; 95% CI: 1.35-9.92; p = 0.01) responded better to therapy, which was different from the results of some studies included. CONCLUSION: Individuals with the TNF-α-308 G allele and -857 C allele showed better anti-TNF-α treatment responses than those with the TNF-α-308 A allele and -857 T allele. The -308 G/G genotype and -857 C/C genotype are predictors of good response.

[Efficacy of ginsenosides combined with prednisone in patients with systemic lupus erythematosus: a prospective, randomized, double-blind, placebo-controlled trial].

BACKGROUND: The side effects of glucocorticoid in treatment of systemic lupus erythematosus (SLE) have been the focus of debate, and our preliminary study indicates that ginsenosides can enhance the efficacy of dexamethasone. OBJECTIVE: To observe the effects of ginsenosides combined with prednisone in SLE patients. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A total of 60 SLE patients from Department of Rheumatology and Immunology, Changhai Hospital, Second Military Medical University, were randomly divided into treatment group and control group, with 30 patients in each group. Patients in the treatment group were given routine treatment with prednisone plus ginsenosides, while those in the control group were given routine treatment with prednisone plus placebo. They were all treated for 3 months. MAIN OUTCOME MEASURES: After three-month treatment, syndrome score in traditional Chinese medicine (TCM), total response rate and symptom improvement rate were measured and evaluated. RESULTS: Twenty-eight cases in treatment group and twenty-seven cases in control group were included in analysis. The total response rates in the treatment group and control group were 89.28% and 66.67% respectively, and there was a significant difference between the two groups (P<0.05). After treatment, the TCM syndrome scores in the two groups were lower than those before treatment (P<0.01), and prednisone plus ginsenosides was better in decreasing the TCM syndrome score than prednisone plus placebo (P<0.05). The symptoms were improved in the treatment group as compared with the control group (P<0.05). CONCLUSION: Prednisone combined with ginsenosides can increase the clinical effective rate and improve the clinical symptoms of SLE patients.