Tumor necrosis factor receptor-associated factor 6 promotes migration of rheumatoid arthritis fibroblast-like synoviocytes

Wang, Huiqin; Chen, Weixia; Li, Faxin; Zhang, Chunyu; Liu, Xu

doi:10.3892/mmr.2014.3104

Cited by 17 publications

(13 citation statements)

References 26 publications

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“…The mortality rate in patients with RA in China is 0.32-0.36% which is slightly lower than that of the global average (5). Due to its chronic nature and high disability rates, 75% patients with RA would become disabled in 3 years without effective and timely treatment (21). In the present study, treatment with >1 mg/kg LLDT-8 significantly reduced the clinical arthritis scores in a rat model of CIA.…”

Section: Discussionmentioning

confidence: 45%

(5R)-5-hydroxytriptolide (LLDT-8) prevents collagen-induced arthritis through OPG/RANK/RANKL signaling in a rat model of rheumatoid arthritis

Zeng

Meng

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. (5R)-5-hydroxytriptolide (LLDT-8) extracts fromTripterygium have anti-inflammatory, antineoplastic and immunity adjustment functions. The present study used a collagen-induced arthritis (CIA) model to evaluate whether LLDT-8 prevents collagen-induced arthritis, and investigated the signaling underlying this. Male Sprague-Dawley rats were induced to generate CIA, mimicking rheumatoid arthritis (RA). The presence of arthritis was determined using RA progression scores. The inflammatory cytokines interleukin (IL)-1β, IL-6 and nuclear factor-κB were detected using enzyme-linked immunosorbent assay kits. Induced nitric oxide synthase (iNOS) and matrix metalloprotease (MMP)-13 protein expression were measured using western blot analysis. Lastly, reverse transcription-quantitative polymerase chain reaction was used to evaluate osteoprotegerin (OPG) and receptor activator of nuclear factor κB (RANK) gene expression. LLDT-8 improved RA progression scores and reduced the incidence and severity of CIA. Furthermore, LLDT-8 administration inhibited collagen-induced inflammation and iNOS protein expression in arthritic rats. The current data indicated that MMP-13 production was suppressed and OPG/RANKL expression was increased by LLDT-8 treatment in the arthritic rat. The present results suggest that LLDT-8 attenuates CIA through OPG/RANK/RANK ligand signaling in a rat model of RA. IntroductionRheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that is characterized by erosive arthrosynovitis (1).The incidence of RA in females is more than that in males, at a ratio of 1:3 (2). The mortality rate of RA in worldwide populations varies from 0.01-0.05%, and prevalence rate is 0.18-1.07% (3). RA is also an impactful disease, resulting in labor loss and disability in China (2). According to US epidemiological investigation over the last 40 years, the difference in mortality rate between RA patients and the general population has increased (4). The risk of cognitive impairment for RA patients is higher than that of the general population (5). The etiology of RA is unclear. Previous studies suggest that RA is associated with genetic factors, infection, immunity and endocrine function (6,7).The main pathological characteristics of RA are hyperplasia of synovial cells and T cell accumulation during inflammation of synovial tissues, accompanied by pannus formation, followed by damage to the cartilage and bone (8). Finally, RA causes joint deformity and functional loss (9). These pathological changes may result from a combination of genetic mutations, activation of protooncogenes, lesions of synoviocytes, release of proinflammatory cytokines by inflammatory cells during infiltration of synovial tissues, chemotactic factors and enzymatic degradation of stromal proteins, amongst other factors (10). The etiology of RA is unclear, but it is universally believed to be a multifactorial disease, associated with genetic, environmental and infective factors (11). Autoimmunity may arise due to genetic factors, or as an ab...

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Section: Discussionmentioning

confidence: 45%

(5R)-5-hydroxytriptolide (LLDT-8) prevents collagen-induced arthritis through OPG/RANK/RANKL signaling in a rat model of rheumatoid arthritis

Zeng

Meng

et al. 2016

Experimental and Therapeutic Medicine

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“…Overexpression of TRAF6 as well as enhanced TRAF6 activity have been shown to promote chronic immune stimulation in a variety of disorders, including autoimmunity, inflammation, and cancer (8). For example, it has previously been demonstrated that TRAF6 expression is elevated in rheumatoid arthritis (RA) patients (16,17) and in lupus cohorts (18). On a molecular level, disruption of TRAF6 -Ubc13 binding by the cellular protein A20 (19) or by genetic mutations (20,21) counteracts TRAF6 activity and NF-B activation.…”

Section: Constitutive Nf-b Signaling Represents a Hallmark Of Chronicmentioning

confidence: 99%

Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity

Brenke

Popowicz

Schorpp

et al. 2018

Journal of Biological Chemistry

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Constitutive NF-κB signaling represents a hallmark of chronic inflammation and autoimmune diseases. The E3 ligase TNF receptor-associated factor 6 (TRAF6) acts as a key regulator bridging innate immunity, pro-inflammatory cytokines, and antigen receptors to the canonical NF-κB pathway. Structural analysis and point mutations have unraveled the essential role of TRAF6 binding to the E2-conjugating enzyme ubiquitin-conjugating enzyme E2 N (Ubc13 or UBE2N) to generate Lys-linked ubiquitin chains for inflammatory and immune signal propagation. Genetic mutations disrupting TRAF6-Ubc13 binding have been shown to reduce TRAF6 activity and, consequently, NF-κB activation. However, to date, no small-molecule modulator is available to inhibit the TRAF6-Ubc13 interaction and thereby counteract NF-κB signaling and associated diseases. Here, using a high-throughput small-molecule screening approach, we discovered an inhibitor of the TRAF6-Ubc13 interaction that reduces TRAF6-Ubc13 activity both and in cells. We found that this compound, C25-140, impedes NF-κB activation in various immune and inflammatory signaling pathways also in primary human and murine cells. Importantly, C25-140 ameliorated inflammation and improved disease outcomes of autoimmune psoriasis and rheumatoid arthritis in preclinical mouse models. Hence, the first-in-class TRAF6-Ubc13 inhibitor C25-140 expands the toolbox for studying the impact of the ubiquitin system on immune signaling and underscores the importance of TRAF6 E3 ligase activity in psoriasis and rheumatoid arthritis. We propose that inhibition of TRAF6 activity by small molecules represents a promising novel strategy for targeting autoimmune and chronic inflammatory diseases.

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“…TRAF6 assists in the maturity of DC-mediated signal transduction and is a key to DC formation, activation, and maturation (20)(21)(22). Thus, to explore specific interventions of TRAF6 expression is essential, which inhibits DC maturation, reconstructs RA immune tolerance, and plays a therapeutic role (23,24).…”

Section: Discussionmentioning

confidence: 99%

TRAF6 regulates the effects of polarized maturation of tolerability: Marrow-derived dendritic cells on collagen-induced arthritis in mice

et al. 2017

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Abstract. The study aimed to investigate the re lationship between tumor necrosis factor receptor-associated factor 6 (TRAF6) and a differentially mature dendritic cell (mDC) in collagen-induced arthritis (CIA) mice and to determine whether or not TRAF6 regulates the activation of an immature dendritic cell (iDC) and inhibits iDC maturation to induce immune tolerance. The mouse bone marrow stem cells were induced with recombinant granulocyte-macrophage colony-stimulating factor (rmGM-CSF) and recombinant interleukin-4 (rmIL-4) to differentiate immature dendritic cells (DCs), which were divided into four groups with different maturation states: rmGM-CSF, rmIL-4; TNF-α; LPS; and FK506 group. The levels of the cell surfaces of CD80, CD86, and MHI-Ⅱ were analyzed by flow cytometry to prove DCs at different levels of maturity. The expression of IL-12 in DCs at different maturation states was detected by enzyme-linked immunosorbent assay (ELISA). The expression of TRAF6 mRNA and protein in each group of DCs was detected by a reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. The results revealed that the differentiation of bone marrow cells into iDCs was significantly induced by cytokines (rmGM-CSF, IL-4). CD80, CD86, MHC-Ⅱ were expressed in the four groups, and the difference between them was statistically significant (P<0.05). A higher degree of DC differentiation led to a gradual increase of IL-12 secretion in the four groups. The difference was statistically significant (P<0.05) for this secretion (group D, 10,620.73±276.73 pg/ml). The exp ression levels of TRAF6 mRNA were significantly higher in group D than those in the other three groups (P<0.01). Although there was no significant difference in the expression levels of TRAF6 mRNA between groups B and C, the expression levels of TRAF6 mRNA between groups B and C were higher than those of the control group. The TRAF6 protein expression was higher in group D than that in the other three groups (P<0

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Tumor necrosis factor receptor-associated factor 6 promotes migration of rheumatoid arthritis fibroblast-like synoviocytes

Cited by 17 publications

References 26 publications

(5R)-5-hydroxytriptolide (LLDT-8) prevents collagen-induced arthritis through OPG/RANK/RANKL signaling in a rat model of rheumatoid arthritis

(5R)-5-hydroxytriptolide (LLDT-8) prevents collagen-induced arthritis through OPG/RANK/RANKL signaling in a rat model of rheumatoid arthritis

Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity

TRAF6 regulates the effects of polarized maturation of tolerability: Marrow-derived dendritic cells on collagen-induced arthritis in mice

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