scholarly journals AB0043 EFFECT OF ANTI-INFLAMMATORY MEDICATION ON INTERACTION OF SYNOVIAL FIBROBLASTS WITH MACROPHAGES IN RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1054.1-1054
Author(s):  
M. Schmeller ◽  
M. Diller ◽  
R. Hasseli ◽  
A. Knothe ◽  
S. Rehart ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mononuclear Cells ◽  
Joint Inflammation ◽  
Synovial Fibroblasts ◽  
Therapeutic Effects ◽  
Synergistic Activity ◽  
M1 Macrophages ◽  
Healthy Donors ◽  
Proinflammatory Activity ◽  
Anti Inflammatory

Background:One of the key mechanisms in the pathogenesis of rheumatoid arthritis (RA) is the interaction of macrophages and synovial fibroblasts during joint inflammation. Increased synergistic proinflammatory activity of both cell types leads to the release of high levels of proinflammatory cytokines, especially of interleukin-6 (IL-6), and of matrix degrading enzymes. If this mechanism is uncontrolled, progressive destruction of articular cartilage and bone will take place.In active disease, immediate anti-inflammatory treatment with glucocorticoids is usually replaced by disease-modifying anti-rheumatic drugs (DMARDS), especially by methotrexate (MTX) and biologics such as TNF-α- or IL-6-inhibitors. This led to great improvements in prognosis and outcome for RA patients. However, about 40% of patients experience no remission or suffer from side effects of medication. To optimize established substances and to develop new treatment strategies, it is necessary to understand the mechanisms underlying the limited therapeutic effects.Objectives:Evaluation of the effect of prednisolone, MTX, adalimumab, tocilizumab on IL-6 secretion by RA synovial fibroblasts (RASF) and macrophages.Methods:RA synovium was used for RASF isolation. Peripheral blood mononuclear cells (PBMCs) were isolated from blood of healthy donors and RA patients by using Ficoll© medium followed by density gradient centrifugation. Mononuclear cells were seeded on six well plates (6x10^6/well) and incubated for one week. Then they were stimulated with Interferon-у (20 ng/ml) and LPS (50 ng/ml) for 48h to initiate differentiation into proinflammatory M1 macrophages. The M1 macrophages were co-cultured with RASF (100.000/well) and different treatments added (prednisolone: 10, 25, 50, 75, 100 nM, 1 µM; adalimumab: 100, 500 µg/ml; tocilizumab: 1, 5 µg/ml; MTX: 0,5, 1, 5, 10, 100 nM, 1µM). After 24h culture supernatants were collected and IL-6- and TNFα-ELISAs were performed.Results:IL-6 concentrations of untreated controls were comparable, regardless whether M1 macrophages from healthy donors or RA-patients were used for co-culture. Prednisolone reduced co-culture-induced IL-6 up to 56% (p<0.001) in co-culture of RASF and M1 macrophages of healthy donors and up to 60% (p<0.001) in co-culture of RASF and RA M1 macrophages. Adalimumab reduced IL-6 up to 28% (p<0.05) in M1 of healthy donors and up to 45% (p<0.01) in RA M1 macrophage co-cultures. A minor reduction by 10-20% of IL-6 was observed with tocilizumab and no significant effect could be achieved after treatment with MTX.Conclusion:Prednisolone and adalimumab clearly decrease but do not eliminate proinflammatory synergistic activity of RASF and M1 macrophages. These results confirm the clinical observation, that there is a large number of RA-patients that independent of anti-inflammatory treatment still suffer from low-level joint inflammation.The synergistic proinflammatory activity of M1 macrophages and RASF seems to be a complex and multifactorial mechanism that is difficult to eliminate by a single treatment substance. Since it is one of the key mechanisms in RA pathogenesis, there is a critical need to investigate how therapy effects could be optimized. This study confirmed RASFs as one of the leading effector cells of increased synergistic proinflammatory activity, thus underlining their promising role as a treatment target in rheumatoid arthritis.Disclosure of Interests:None declared

scholarly journals Prostacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis

2006 ◽  
Vol 203 (2) ◽  
pp. 325-335 ◽  
Author(s):  
Tetsuya Honda ◽  
Eri Segi-Nishida ◽  
Yoshiki Miyachi ◽  
Shuh Narumiya
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
Joint Inflammation ◽  
Synovial Fibroblasts ◽  
The Other ◽  
Receptor Subtype ◽  
Significant Suppression ◽  
Wild Type ◽  
Collagen Induced Arthritis

Prostaglandin (PG)I2 (prostacyclin [PGI]) and PGE2 are abundantly present in the synovial fluid of rheumatoid arthritis (RA) patients. Although the role of PGE2 in RA has been well studied, how much PGI2 contributes to RA is little known. To examine this issue, we backcrossed mice lacking the PGI receptor (IP) to the DBA/1J strain and subjected them to collagen-induced arthritis (CIA). IP-deficient (IP−/−) mice exhibited significant reduction in arthritic scores compared with wild-type (WT) mice, despite anti-collagen antibody production and complement activation similar to WT mice. IP−/− mice also showed significant reduction in contents of proinflammatory cytokines, such as interleukin (IL)-6 in arthritic paws. Consistently, the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced IL-6 production and induced expression of other arthritis-related genes. On the other hand, loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA. However, a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4. Our results show significant roles of both PGI2-IP and PGE2-EP2/EP4 signaling in the development of CIA, and suggest that inhibition of PGE2 synthesis alone may not be sufficient for suppression of RA symptoms.

scholarly journals Liposome/gold hybrid nanoparticle encoded with CoQ10 (LGNP-CoQ10) suppressed rheumatoid arthritis via STAT3/Th17 targeting

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241080
Author(s):  
Jooyeon Jhun ◽  
Jeonghyeon Moon ◽  
Jaeyoon Ryu ◽  
Yonghee Shin ◽  
Seangyoun Lee ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mononuclear Cells ◽  
Therapeutic Potential ◽  
Human Peripheral Blood ◽  
Treated Group ◽  
Hybrid Nanoparticles ◽  
Peripheral Blood Mononuclear ◽  
Hematoxylin And Eosin ◽  
Anti Inflammatory ◽  
Safranin O

Coenzyme Q10 (CoQ10), also known as ubiquinone, is a fat-soluble antioxidant. Although CoQ10 has not been approved as medication by the Food and Drug Administration, it is widely used in dietary supplements. Some studies have shown that CoQ10 has anti-inflammatory effects on various autoimmune disorders. In this study, we investigated the anti-inflammatory effects of liposome/gold hybrid nanoparticles encoded with CoQ10 (LGNP-CoQ10). Both CoQ10 and LGNP-CoQ10 were administered orally to mice with collagen-induced arthritis (CIA) for 10 weeks. The inflammation pathology of joint tissues of CIA mice was then analyzed using hematoxylin and eosin and Safranin O staining, as well as immunohistochemistry analysis. We obtained immunofluorescence staining images of spleen tissues using confocal microscopy. We found that pro-inflammatory cytokines were significantly decreased in LGNP-CoQ10 injected mice. Th17 cell and phosphorylated STAT3-expressed cell populations were also decreased in LGNP-CoQ10 injected mice. When human peripheral blood mononuclear cells (PBMCs) were treated with CoQ10 and LGNP-CoQ10, the IL-17 expression of PBMCs in the LGNP-CoQ10-treated group was significantly reduced. Together, these results suggest that LGNP-CoQ10 has therapeutic potential for the treatment of rheumatoid arthritis.

scholarly journals Therapeutic Potential of a Novel Bifidobacterium Identified Through Microbiome Profiling of RA Patients With Different RF Levels

2021 ◽  
Vol 12 ◽  
Author(s):  
Yunju Jeong ◽  
JooYeon Jhun ◽  
Seon-Yeong Lee ◽  
Hyun Sik Na ◽  
JeongWon Choi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Relative Abundance ◽  
Th17 Cells ◽  
Mononuclear Cells ◽  
Therapeutic Potential ◽  
Human Peripheral Blood ◽  
Cartilage Damage ◽  
Therapeutic Effects ◽  
Bioinformatics Analyses ◽  
Proinflammatory Mediators

The potential therapeutic effects of probiotic bacteria in rheumatoid arthritis (RA) remain controversial. Thus, this study aimed to discover potential therapeutic bacteria based on the relationship between the gut microbiome and rheumatoid factor (RF) in RA. Bacterial genomic DNA was extracted from the fecal samples of 93 RA patients and 16 healthy subjects. Microbiota profiling was conducted through 16S rRNA sequencing and bioinformatics analyses. The effects of Bifidobacterium strains on human peripheral blood mononuclear cells and collagen-induced arthritis (CIA) mice were assessed. Significant differences in gut microbiota composition were observed in patients with different RF levels. The relative abundance of Bifidobacterium and Collinsella was lower in RF-high than in RF-low and RF-negative RA patients, while the relative abundance of Clostridium of Ruminococcaceae family was higher in RF-high than in RF-low and RF-negative patients. Among 10 differentially abundant Bifidobacterium, B. longum RAPO exhibited the strongest ability to inhibit IL-17 secretion. Oral administration of B. longum RAPO in CIA mice, obese CIA, and humanized avatar model significantly reduced RA incidence, arthritis score, inflammation, bone damage, cartilage damage, Th17 cells, and inflammatory cytokine secretion. Additionally, B. longum RAPO significantly inhibited Th17 cells and Th17-related genes—IL-17A, IRF4, RORC, IL-21, and IL-23R—in the PBMCs of rheumatoid arthritis patients. Our findings suggest that B. longum RAPO may alleviate RA by inhibiting the production of IL-17 and other proinflammatory mediators. The safety and efficacy of B. longum RAPO in patients with RA and other autoimmune disorders merit further investigation.

Fibroblasts and mesenchymal cells

2013 ◽  
pp. 379-385
Author(s):  
Andrew Filer ◽  
Maria Juarez ◽  
Christopher Buckley
Keyword(s):  
Rheumatoid Arthritis ◽  
Wound Healing ◽  
Joint Destruction ◽  
Joint Inflammation ◽  
Synovial Fibroblasts ◽  
Mesenchymal Cells ◽  
Structure And Function ◽  
Epigenetic Programming ◽  
Disease Initiation ◽  
And Function

In order to understand and explore the function and roles of fibroblasts, it is necessary to understand their lineage relationships to other mesenchymal cells. Fibroblasts are ubiquitous non-epithelial, non-endothelial, and non-haematopoietic adherent cells that have the capacity to produce and remodel extracellular matrix. In addition to their well-known ’landscaping’ function which determines the unique structure and function of different organs, they play an important role in wound healing, immune tolerance, and disease. In cancer, epithelial-stromal interactions have been implicated in disease initiation and progression. In rheumatoid arthritis, synovial fibroblasts at diseased sites become persistently activated and behave abnormally, orchestrating joint inflammation and contributing to joint destruction. Recent evidence suggests that the activated phenotype of fibroblasts in pathology may result from epigenetic programming, which is becoming a major focus for development of new therapeutics.

scholarly journals P201 Anti-inflammatory and immunologic actions of pinolenic acid in rheumatoid arthritis

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Rabaa Takala ◽  
Dipak Ramji ◽  
Ernest Choy
Keyword(s):  
Rheumatoid Arthritis ◽  
Flow Cytometry ◽  
Mononuclear Cells ◽  
Vehicle Control ◽  
Boyden Chamber ◽  
Pinolenic Acid ◽  
Human Macrophages ◽  
Monocyte Migration ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract Background Rheumatoid arthritis (RA) is a common inflammatory arthritis. Although advanced targeted therapies have improved prognosis, many patients seek advice on dietary intervention that may improve symptoms. Pinolenic acid (PNLA) is a polyunsaturated fatty acid found in pine nuts. We investigated the anti-inflammatory effects of 25-100 μM PNLA on cell line, primary culture, and peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy controls (HCs). Methods 1- Migration using modified Boyden Chambers: THP-1 monocytes incubated with vehicle or PNLA were added to the apical compartment of a modified Boyden chamber. The migration of the cells through inserts of 8 μm pore size in response to the chemokine monocyte chemoattractant protein-1 (MCP-1) added to basolateral (bottom) chamber was determined. 2- Macropinocytosis using Lucifer yellow (LY): THP-1 and primary human macrophages were pre-incubated with PNLA or vehicle control followed by LY. After incubation, cells were removed, fixed and assessed by flow cytometry. 3- Lipid uptake using Dil-oxidised low-density lipoprotein (Dil-oxLDL): THP-1 and primary macrophages were pre-incubated with PNLA or vehicle control followed by Dil-oxLDL. After incubation, cells were removed, fixed and assessed by flow cytometry. 4- Cytokines release by lipopolysaccharide (LPS) stimulated PBMCs: PBMCs were isolated from blood obtained from RA patients aged ≥18 years and HCs. Monocytes were purified and cultured with PNLA or vehicle control. Cells were stimulated with LPS. IL-6, TNF-α, IL-1β and prostaglandin E2 (PGE2) in the supernatant were assessed by ELISAs. For macrophages, monocytes were left to grow and differentiate over 10 days, the differentiated macrophages were treated with PNLA or vehicle and activated with LPS and assayed in identical conditions for monocytes. Results PNLA at all concentrations reduced THP-1 monocytes migration by average of 55% (p &lt; 0.001) when compared with vehicle controls. Macropinocytosis of THP-1 macrophages and human macrophages were reduced by almost 50% (p &lt; 0.001) and 45% (p &lt; 0.001) respectively by PNLA. Similarly, Dil-oxLDL uptake by THP-1 macrophages and primary macrophages were reduced by 40% (p &lt; 0.01) and 25% (p &lt; 0.05) respectively by 25 μM PNLA. Release of IL-6 and TNF-α by LPS stimulated monocytes in RA patients were reduced with 25 and 50 μM PNLA by 60% (p &lt; 0.001) and in HC by 50% and 35% respectively (p &lt; 0.01). PGE2 levels were inhibited by the same percentage in both HC and RA monocytes (p &lt; 0.001) by 50 μM PNLA. Similarly, effects were observed with IL-6, TNF- α, and PGE2 levels in LPS-stimulated macrophages especially in RA patients 30% (p &lt; 0.05). Conclusion Our data suggest that PNLA significantly attenuated monocyte migration, significantly reduced macropinocytosis and Dil-oxLDL uptake in macrophages. Furthermore, PNLA inhibited production of IL-6, TNF-α and PGE2 levels in LPS-stimulated monocytes and macrophages from RA patients. These data inform on the potential anti-inflammatory and analgesic effects of PNLA. Disclosures R. Takala None. D. Ramji None. E. Choy None.

Anti-inflammatory effects of ursolic acid-3-acetate on human synovial fibroblasts and a murine model of rheumatoid arthritis

2017 ◽  
Vol 49 ◽  
pp. 118-125 ◽  
Author(s):  
Jong Yeong Lee ◽  
Jin Kyeong Choi ◽  
Na-Hee Jeong ◽  
Jeongsoo Yoo ◽  
Yeong Su Ha ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Ursolic Acid ◽  
Murine Model ◽  
Synovial Fibroblasts ◽  
Anti Inflammatory

scholarly journals Inhibitory Effect of a Novel Antirheumatic Drug T-614 on the IL-6-Induced RANKL/OPG, IL-17, and MMP-3 Expression in Synovial Fibroblasts from Rheumatoid Arthritis Patients

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Yu Wei ◽  
Xiaoxun Sun ◽  
Minhui Hua ◽  
Wenfeng Tan ◽  
Fang Wang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Inflammation ◽  
Synovial Fibroblasts ◽  
Inhibitory Effect ◽  
Antirheumatic Drug ◽  
Orphan Receptor ◽  
Rankl Expression ◽  
Articular Damage ◽  
Receptor Activator

T-614 (also named as iguratimod), a novel antirheumatic drug, could attenuate joint inflammation and articular damage in rheumatoid arthritis (RA) patients, providing a new therapy for RA. Here, we tested the role T-614 on the IL-6-induced receptor activator of nuclear factorκB ligand (RANKL)/osteoprotegerin (OPG), IL-17, and MMP-3 expression in synovial fibroblasts from rheumatoid arthritis (RASFs) patients. T-614 decreased RANKL expression and RANKL/OPG ratio in IL-6-induced RASFs. We confirmed this effect by a decrease of the mRNA and protein RANKL and mRNA RANKL/OPG in RASFs exposed in vitro to T-614 or MTX. Markedly decreased levels of IL-17, retinoid-related orphan receptor C (RORc), and MMP-3 mRNA expression were also observed in IL-6-induced RASFs in the presence of T-614 or MTX compared with those in its absence. Furthermore, T-614 blocked expression of p-ERK1/2 protein without affecting ERK1/2 expression, indicating that the way that T-614 regulated RANKL expression might be ERK1/2 pathway. Our results suggest that T-614 yields a strong improvement in arthritis via exact suppression of RANKL/OPG, IL-17, and MMP-3 expression in RASFs.

scholarly journals Sec-O-glucosylhamaudol suppressed inflammatory reaction induced by LPS in RAW264.7 cells through inhibition of NF-κB and MAPKs signaling

2020 ◽  
Vol 40 (2) ◽  
Author(s):  
Guiming Liu ◽  
Jing Xie ◽  
Yurui Shi ◽  
Rongda Chen ◽  
Li Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bioactive Compound ◽  
Therapeutic Effects ◽  
Raw 264.7 ◽  
Pcr Assay ◽  
Raw 264.7 Cell ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Saposhnikovia Divaricata ◽  
Inflammation Cytokines

Abstract As a major bioactive compound from the Saposhnikovia divaricata (Turcz.) Schischk, sec-O-glucosylhamaudol (SOG), has been reported to have anti-nociceptive activity and high 5-lipoxygenase (5-LOX) activity. Nevertheless, the mechanism of the potential anti-inflammatory effects of SOG is unclear. The anti-inflammatory impacts of SOG in RAW 264.7 cell lines stimulated by LPS were explored in the present study. It was found that SOG dose-dependently reduced the emergence of inflammation cytokines, such as IL-6 and TNF-α in Raw264.7 murine macrophages stimulated by LPS. Real-time PCR assay demonstrated the SOG dose-dependently inhibited transcription of these cytokines as well. In addition, it was also found that NF-κB activation and MAPKs phosphorylation including p38, JNK and ERK1/2 induced by LPS were suppressed by SOG. Due to its anti-inflammatory activity, our results suggest that SOG might have therapeutic effects on inflammatory disease, such as acute lung injury or rheumatoid arthritis.

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