Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis

Interleukin (IL)-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines. However, the role of the IL-18/IL-18 receptor-alpha (Rα) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18Rα knockout (KO) mice were immunized with bovine type II collagen before the onset of arthritis induced by lipopolysaccharide injection. Disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum inflammatory cytokine and anticollagen antibody levels were quantified by an enzyme-linked immunosorbent assay. Joint cytokine and matrix metalloproteinases-3 levels were determined by a quantitative polymerase chain reaction. Splenic suppressors of cytokine signaling (SOCS) were determined by Western blot analysis as indices of systemic immunoresponse. IL-18Rα KO mice showed lower arthritis and histological scores in bone erosion and synovitis due to reductions in the infiltration of CD4+ T cells and F4/80+ cells and decreased serum IL-6, -18, TNF, and IFN-γ levels. The mRNA expression and protein levels of SOCS3 were significantly increased in the IL-18Rα KO mice. By an up-regulation of SOCS, pro-inflammatory cytokines were decreased through the IL-18/IL-18Rα signaling pathway. These results suggest that inhibitors of the IL-18/IL-18Rα signaling pathway could become new therapeutic agents for rheumatoid arthritis.

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AB0103 THE AMBIGUOUS ROLE OF TISSUE CYTOKINES IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1226 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1350.1-1351

Author(s):

O. Korolik ◽

В. Zavodovsky ◽

E. Papichev ◽

Y. Polyakova ◽

S. L ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

High Activity ◽

Inflammatory Cytokines ◽

Stage Iii ◽

Enzyme Linked Immunosorbent Assay ◽

Healthy Individuals ◽

Fetuin A ◽

High Level ◽

Extraarticular Manifestations ◽

Pro Inflammatory Cytokines

Background:Cytokines stimulate the inflammatory response in the synovial membrane with rheumatoid arthritis (RA), initiate apoptosis of chondrocytes, activation of osteoclasts. The progression of comorbid diseases is also associated with the influence of cytokines. At the same time, anti-inflammatory cytokines are produced in various tissues. Their role in the pathogenesis of RA and its complications is ambiguous.Adiponectin (A) and Fetuin A (FA) are classified as negative acute phase proteins. Their concentration decreases with an increase in the level of pro-inflammatory cytokines: TNF-α, IL-1 and IL-6. Molecules A and FA, regardless of various factors and from each other, have similar effects in relation to pro-inflammatory cytokines, lipid and carbohydrate metabolism.Visfatin (V) and Nesfatin-1 (N-1) are pro-inflammatory adipokines. B is produced by cells of the mononuclear phagocytic system and connective tissue. N-1 - is produced by the cells of the intermediate and medulla oblongata and by the cells of the gastric mucosa.Objectives:to study the correlation of B, H-1, A and FA with the severity of inflammation in RAMethods:60 patients with RA and 30 healthy individuals were examined. The level of cytokines was determined by an indirect enzyme-linked immunosorbent assay using commercial test systems (Bio Vendor, cat No. RD195023100, Bio Vendor Human Fetuin-A, RaiBiotech, cat No. EIA-VIS-1, RaiBiotech, cat No. EIA-NESF). All patients underwent a full examination. Diagnosed with 2010 EULAR / ACR recommendations.Results:A decreased level of A (less than 0.8 μg/ml) was detected in 15 patients (25%), F-A (less than 653.55 μg/ml) in 16 (27%), a high level of V (more than 39 ng/ml) - in 55 (91%), N-1 (more than 37.95 ng/ml) - in 36 (60%), which is significantly more often than in healthy individuals. No significant difference in the levels of determined adipokines was found depending on the gender and body weight of patients with RA. The level of cytokines in RA is associated with high activity according to DAS 28, positivity by Anti-CCP, extraarticular manifestations of RA. The greatest correlation with extraarticular manifestations is with cutaneous and cerebral vasculitis. The levels of FA and N-1 also correlated with more pronounced radiological changes (X-ray stage III). FA circulating inhibitor of ectopic calcification. N-1 level is positively correlated with systolic blood pressure.Conclusion:A low level of A and FA, a high level of V and N-1 is characteristic of RA with the presence of high activity and positivity in the RF and Anti-CCP. An increased level of B is determined by more than 90% of patients, which indicates its high pro-inflammatory activity. The level of F and N-1 is also associated with the degree of damage to bone tissue (stage III, a lot of erosion). A positive correlation of level V and N-1, negative A and FA with the severity of inflammation in RA confirms the involvement of these proteins in the pathogenesis. A high level of A and V increases the risk of developing cardiovascular diseases and their complications, the effect of N-1 and FA is being studied. The effect of cytokines on osteoclasts and osteoblasts in RA is ambiguousReferences:[1]Visfatin and Rheumatoid Arthritis: Pathogenetic Implications and Clinical Utility. Polyakova Y. Curr Rheumatol Rev.2019[2]Serum nesfatin -1 as a marker of systemic inflammation in rheumatoid arthritis. Kvlividze T. Klinicheskaya Laboratornaya Diagnostika.2019; 64 (1):53-56 (in Russ)[3]Fetuin-A. Novel hepatokine in rheumatoid arthritis laboratory diagnostics. Papichev E. Klinicheskaya Laboratornaya Diagnostika.2018; 63 (12):756-760 (in Russ)Disclosure of Interests:None declared

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Inhibition of Rheumatoid Arthritis Using Bark, Leaf, and Male Flower Extracts of Eucommia ulmoides

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/3260278 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Yun-Yun Xing ◽

Jian-Ying Wang ◽

Kai Wang ◽

Yan Zhang ◽

Kun Liu ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Bone Erosion ◽

Bone Destruction ◽

Male Flower ◽

Joint Inflammation ◽

Inflammatory Factors ◽

Enzyme Linked Immunosorbent Assay ◽

Eucommia Ulmoides

Eucommia ulmoides Oliv., a native Chinese plant species, has been used as a traditional Chinese medicine formulation to treat rheumatoid arthritis (RA), strengthen bones and muscles, and lower blood pressure. Various parts of this plant such as the bark, leaves, and flowers have been found to have anti-inflammatory properties. E. ulmoides has potential applications as a therapeutic agent against bone disorders, which were investigated in this study. In vitro, RA joint fibroblast-like synoviocytes (RA-FLS) were treated with different concentrations (0, 25, 50, 100, 200, 400, 800, and 1000 μg/mL) of E. ulmoides bark, leaf, and male flower alcoholic extracts (EB, EL, and EF, respectively) to determine their potential cytotoxicity. Tumor necrosis factor- (TNF-) α and nitric oxide (NO) levels in RA-FLS were quantified using enzyme-linked immunosorbent assay (ELISA). Furthermore, collagen-induced arthritis (CIA) rats were treated with EB, EL, EF, Tripterygium wilfordii polyglycoside (TG) or the normal control (Nor), and then ankle joint pathology, bone morphology, and serum and spleen inflammatory cytokine levels were evaluated. The results showed that, in RA-FLS, EB, EL, and EF were not cytotoxic; EB and EF reduced TNF-α supernatant levels; and EB, EL, and EF reduced NO levels. The results of in vivo experiments showed that EB, EL, and EF alleviated ankle swelling and joint inflammation, while all extracts diminished inflammatory cell infiltration, pannus and bone destruction, and bone erosion. All tested extracts inhibited interleukin- (IL-) 6, IL-17, and TNF-α mRNA in the spleen of CIA rats, while EB most effectively reduced osteoclasts and inhibited bone erosion. EF showed the most obvious inhibition of inflammatory factors and pannus. Thus, EB, EL, and EF may alleviate bone destruction by inhibiting inflammation.

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Effect of 1,25-(OH)2D3 on Proliferation of Fibroblast-Like Synoviocytes and Expressions of Pro-Inflammatory Cytokines through Regulating MicroRNA-22 in a Rat Model of Rheumatoid Arthritis

Cellular Physiology and Biochemistry ◽

10.1159/000477123 ◽

2017 ◽

Vol 42 (1) ◽

pp. 145-155 ◽

Cited By ~ 13

Author(s):

Ping Fan ◽

Lan He ◽

Nan Hu ◽

Jing Luo ◽

Jing Zhang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Inflammatory Cytokines ◽

Rat Model ◽

Type Ii Collagen ◽

Proliferation Inhibition ◽

Blank Group ◽

Mtt Method ◽

Cox 2 ◽

Fibroblast Like Synoviocytes ◽

Pro Inflammatory Cytokines

Objective: This study aims to investigate the regulatory mechanism of 1,25-(OH)2D3 on the proliferation of fibroblast-like synoviocytes (FLS) and expressions of pro-inflammatory cytokines in rheumatoid arthritis (RA) rats via microRNA-22 (miR-22). Methods: A rat model of RA was established with a subcutaneous injection of type II collagen. After treated with different concentrations of 1,25-(OH)2D3 the proliferation of FLS was estimated by the MTT method, and the optimal concentration of 1,25-(OH)2D3 was selected for further experiments. Cell proliferation was detected by MTT. Cell cycle and apoptosis were analyzed by FCM. The IL-1β, IL-6, IL-8, and PGE2 protein expressions were determined by ELISA, and MMP-3, INOS, and Cox-2 mRNA expressions were measured by qRT-PCR. Results: The rat model of RA was successfully established. Compared with the blank group, the 1,25-(OH)2D3 and miR-22 inhibitors groups exhibited higher proliferation inhibition and apoptosis rates, lower levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and PGE2), and decreased mRNA expressions of MMP-3, INOS, and Cox-2. The miR-22 mimics group had lower proliferation inhibition and apoptosis rates, elevated expressions of pro-inflammatory cytokines and MMP-3, INOS, and Cox-2 than the blank group. In contrast to the 1,25-(OH)2D3 group, the proliferation inhibition and apoptosis rates were down-regulated, and the expressions of pro-inflammatory cytokines and MMP-3, INOS, and Cox-2 were up-regulated in the 1,25-(OH)2D3 + miR-22 mimics group. Conclusion: Our study demonstrated that 1,25-(OH)2D3 inhibits the proliferation of FLS and alleviates inflammatory response in RA rats by down-regulating miR-22.

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THU0072 THE RELATIONSHIP BETWEEN INFLAMMATION AND COGNITIVE IMPAIRMENT IN RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3985 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 248.1-249

Author(s):

Y. H. Cheon ◽

H. N. Lee ◽

M. Kim

Keyword(s):

Rheumatoid Arthritis ◽

Cognitive Impairment ◽

Inflammatory Cytokines ◽

Joint Inflammation ◽

Peripheral Tissue ◽

Escape Time ◽

Lipocalin 2 ◽

Hippocampal Tissue ◽

Tnf Α ◽

Pro Inflammatory Cytokines

Background:The pathophysiology of cognitive impairment remains unclear, however, several studies have demonstrated that pro-inflammatory cytokines such as Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α) and lipocalin-2 (LCN2) are related with cognitive impairment by activation of microglia and astrocyte in brain. Rheumatoid arthritis (RA) is a representative inflammatory disease; however, the association of pro-inflammatory cytokines and LCN2 with cognitive impairment has seldomly been investigated in RA.Objectives:Here, we determined the effect of pro-inflammatory cytokines and LCN2 on cognitive impairment in collagen-induced arthritis (CIA) mouse model. In addition, we studied the effect of TNF-α inhibitor (etanercept) on cognitive impairment.Methods:We induced CIA mice and randomly divided into three groups: Normal (n=10), CIA group (n=10), CIA/Etanercept group (n=10). We evaluated severity of arthritis using clinical scoring system. Joint inflammation, cartilage damage, and osteoclastic bone resorption has checked. Level of pro-inflammatory cytokines (TNF-α, and IL-6) and LCN2 checked in mice sera using enzyme-linked immunosorbent assay (ELISA). The expression of pro-inflammatory cytokines and LCN2 in ankle and hippocampus analyzed using real-time PCR. The activation of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1) in hippocampus analyzed using immunohistochemistry (IHC). The LCN2 evaluated by western blot using hippocampal tissue. Cognitive impairment determined by morris water maze (MWM) test.Results:Compared to normal group, CIA mice showed increased severity of arthritis, inflammation and destruction of joint. In MWM test, CIA mice significantly exhibited increased escape latencies and escape time, reduced the time in the target quadrant, and the number of target zone crossings during five study days compared with normal group. The level of pro-inflammatory cytokines (TNF-α, IL-6) and LCN2 in both sera, ankle tissue and hippocampal tissue was significantly increased. We examined whether inhibiting inflammation can mitigate the severity of arthritis and cognitive impairment. Compared to CIA mice, CIA/Etanercept group showed decreased severity of arthritis and joint inflammation. In MWM test, CIA/Etanercept group showed reduced escape latencies and escape time, increased the time in the target quadrant and the number of target zone crossings. The level of pro-inflammatory cytokines and LCN2 significantly decreased in both peripheral tissue and hippocampal tissue. In addition, the expression level of GFAP, Iba-1 and inflammatory markers decreased after treatment of etanercept. The results indicated that inhibition of inflammation may improve cognitive impairment.Conclusion:The results suggest that peripheral arthritis induced inflammation is a possible cause for cognitive impairment by increasing pro-inflammatory cytokines and LCN2 in both peripheral tissue and hippocampal tissue in RA. In addition, we indicate that early anti-inflammatory treatment using etanercept may mitigate or inhibit the progression of cognitive impairment in RA.References:[1]Gauthier, S., et al., Mild cognitive impairment. Lancet, 2006.367(9518): p. 1262-70.[2]Belarbi, K., et al., TNF-alpha protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J Neuroinflammation, 2012.9: p. 23.[3]Cunningham, C., et al., Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry, 2009.65(4): p. 304-12.[4]Camara, M.L., et al., Effects of centrally administered etanercept on behavior, microglia, and astrocytes in mice following a peripheral immune challenge. Neuropsychopharmacology, 2015.40(2): p. 502-12.[5]Gulkesen, A., et al., Lipocalin 2 as a clinical significance in rheumatoid arthritis. Cent Eur J Immunol, 2017.42(3): p. 269-273.Disclosure of Interests:None declared

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Heat-killed probiotic bacteria differentially regulate colonic epithelial cell production of human β-defensin-2: dependence on inflammatory cytokines

Beneficial Microbes ◽

10.3920/bm2013.0061 ◽

2014 ◽

Vol 5 (4) ◽

pp. 483-495 ◽

Cited By ~ 23

Author(s):

N. Habil ◽

W. Abate ◽

J. Beal ◽

A.D. Foey

Keyword(s):

Epithelial Cells ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Quantitative Polymerase Chain Reaction ◽

Probiotic Bacteria ◽

Enzyme Linked Immunosorbent Assay ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Probiotic Strains ◽

Pro Inflammatory Cytokines

The inducible antimicrobial peptide human β-defensin-2 (hBD-2) stimulated by pro-inflammatory cytokines and bacterial products is essential to antipathogen responses of gut epithelial cells. Commensal and probiotic bacteria can augment such mucosal defences. Probiotic use in the treatment of inflammatory bowel disease, however, may have adverse effects, boosting inflammatory responses. The aim of this investigation was to determine the effect of selected probiotic strains on hBD-2 production by epithelial cells induced by pathologically relevant pro-inflammatory cytokines and the role of cytokine modulators in controlling hBD-2. Caco-2 colonic intestinal epithelial cells were pre-incubated with heat-killed probiotics, i.e. Lactobacillus casei strain Shirota (LcS) or Lactobacillus fermentum strain MS15 (LF), followed by stimulation of hBD-2 by interleukin (IL)-1β and tumour necrosis factor alpha (TNF-α) in the absence or presence of exogenous IL-10 or anti-IL-10 neutralising antibody. Cytokines and hBD-2 mRNA and protein were analysed by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. LcS augmented IL-1β-induced hBD-2, whereas LF enhanced TNF-α- and suppressed IL-1β-induced hBD-2. LF enhanced TNF-α-induced TNF-α and suppressed IL-10, whereas augmented IL-1β-induced IL-10. LcS upregulated IL-1β-induced TNF-α mRNA and suppressed IL-10. Endogenous IL-10 differentially regulated hBD-2; neutralisation of IL-10 augmented TNF-α- and suppressed IL-1β-induced hBD-2. Exogenous IL-10, however, suppressed both TNF-α- and IL-1β-induced hBD-2; LcS partially rescued suppression in TNF-α- and IL-1β-stimulation, whereas LF further suppressed IL-1β-induced hBD-2. It can be concluded that probiotic strains differentially regulate hBD-2 mRNA expression and protein secretion, modulation being dictated by inflammatory stimulus and resulting cytokine environment.

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Anti-arthritic effect of total anthraquinone from Polygonum cuspidatum on type II collagen-induced arthritis in rats

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v16i10.20 ◽

2017 ◽

Vol 16 (10) ◽

pp. 2453-2459

Author(s):

Feng Wang ◽

Yan-hong Qiao ◽

Hui-min Niu ◽

Hong Zhao

Keyword(s):

Inflammatory Cytokines ◽

Type Ii Collagen ◽

Serum Levels ◽

Underlying Mechanism ◽

Enzyme Linked Immunosorbent Assay ◽

Type Ii ◽

Polygonum Cuspidatum ◽

Collagen Induced Arthritis ◽

Tnf Α ◽

Pro Inflammatory Cytokines

Purpose: To study the anti-arthritic effect of total anthraquinone from Polygonum cuspidatum (TAPC) on type II collagen-induced arthritis (CIA) in rats, and to investigate the underlying mechanism(s).Methods: CIA rats were prepared and treated orally with TAPC at doses of 50, 100 and 200 mg/kg/day, for 24 days. Paw volume and arthritis score were measured prior to TAPC treatment, and subsequently at 3-day intervals on days 3, 6, 9, 12, 15, 18, 21 and 24. Serum levels of TNF-α, IL-6 and IL-17 were determined by enzyme-linked immunosorbent assay (ELISA), while synovial tissue TNF-α, IL-6 and IL-17mRNA expressions were assayed by real time-polymerase chain reaction (RT-PCR). Thymus and spleen indices were also determined.Results: TAPC (50, 100 and 200 mg/kg) significantly alleviated paw swelling (p < 0.05), arthritis scores (p < 0.05) and thymus and spleen indices (p < 0.05) of CIA rats, when compared with the control rats. In addition, TAPC significantly decreased serum levels of the pro-inflammatory cytokines TNF-α, IL-6 and IL-17 (p < 0.01); and down-regulated their mRNA expressions in synovial tissues (p < 0.01).Conclusion: These results suggest that TAPC exerts good anti-arthritic activity in rats, most probably via suppression of inflammatory responses.Keywords: Polygonum cuspidatum, Anthraquinone, Type II collagen-induced arthritis, Pro-inflammatory cytokines

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IRF9 Affects the TNF-Induced Phenotype of Rheumatoid-Arthritis Fibroblast-Like Synoviocytes via Regulation of the SIRT-1/NF-κB Signaling Pathway

Cells Tissues Organs ◽

10.1159/000508405 ◽

2020 ◽

Vol 209 (2–3) ◽

pp. 110-119

Author(s):

Fan Jiang ◽

Hong-Yi Zhou ◽

Li-Fang Zhou ◽

Wei Zeng ◽

Li-Han Zhao

Keyword(s):

Rheumatoid Arthritis ◽

Signaling Pathway ◽

Inflammatory Cytokines ◽

Inhibitory Effect ◽

Migration And Invasion ◽

Enzyme Linked Immunosorbent Assay ◽

Biological Features ◽

Induced Changes ◽

Signaling Activity ◽

Fibroblast Like Synoviocytes

Objective: To discuss how IRF9 affects the fibroblast-like synoviocytes (FLS) in TNF-induced rheumatoid arthritis (RA) via the SIRT-1/NF-κB signaling pathway. Methods: RA-FLS were isolated and divided into control, sh-IRF9, TNF, TNF + sh-Ctrl, TNF + sh-IRF9, TNF + sh-SIRT1, and TNF + sh-IRF9 + sh-SIRT1 groups. Biological features of FLS were evaluated by MTT, wound healing, and Transwell assays, respectively. Cell apoptosis and cycle were assessed flow cytometrically. Inflammatory cytokines were determined through enzyme-linked immunosorbent assay (ELISA), while IRF9 expression and SIRT1/NF-κB signaling pathway activity were measured by Western blotting. Results: TNF increased IRF9 expression as well as NF-κB signaling activity and down-regulated SIRT1 of RA-FLS. Silencing IRF9 resulted in up-regulation of SIRT1 and blocked NF-κB signaling, with significant decreases in TNF-induced cell viability, migration, and invasion, prominent enhancement in apoptosis and the proportion of cells in G0/G1 phase, but a decrease in the proportion of cells in S and G2/M phases, and reduced levels of inflammatory cytokines. However, these changes were totally abolished after silencing SIRT1, i.e., the IRF9 shRNA-induced inhibitory effect on the growth of RA-FLS was reversed. Conclusion: Silencing IRF9 curbs the activity of the NF-κB signaling pathway via up-regulating SIRT-1, to further suppress TNF-induced changes in the malignant features of RA-FLS, and the secretion of inflammatory cytokines, with the promoted apoptosis.

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Evaluating the efficacy of intra-articular injections of platelet rich plasma (PRP) in rheumatoid arthritis patients and its impact on inflammatory cytokines, disease activity and quality of life.

Current Rheumatology Reviews ◽

10.2174/1573397116666201113090629 ◽

2020 ◽

Vol 16 ◽

Author(s):

Dalia S. Saif ◽

Nagwa N. Hegazy ◽

Enas S. Zahran

Keyword(s):

Quality Of Life ◽

Rheumatoid Arthritis ◽

Disease Activity ◽

Inflammatory Cytokines ◽

Platelet Rich Plasma ◽

Joint Inflammation ◽

Monthly Interval ◽

Post Injection ◽

Tnf Α

Background: Among rheumatoid arthritis patients (RA), general disease activity is well regulated by diseasemodifying anti-rheumatic medications (DMARDS), but sometimes local inflammation still persists among a few joints. Adjuvant modern molecular interventions as Platelet Rich Plasma (PRP) with a suggested down regulating effect on inflammatory mediators has a proven effect in management of RA. We aim to evaluate the therapeutic effect of intra-articular PRP versus steroid in RA patients and their impact on inflammatory cytokines IL1B , TNF α, local joint inflammation, disease activity and quality of life (QL). Methods: Open labeled parallel randomized control clinical trial was carried out on 60 RA patients randomly divided into 2 groups, Group 1: included 30 patients received 3 intra-articular injections of PRP at monthly interval, Group 2: included 30 patients received single intra-articular injection of steroid. They were subjected to clinical, laboratory, serum IL1B and TNF α assessment at baseline and at 3, 6 months post injection. Results: Patients of both groups showed improvements in their scores of evaluating tools at 3months post injection and this improvement was persistent in the PRP group up to 6 months post injection while it was continued only for 3 months in the steroid group. Conclusions: PRP is a safe, effective and useful therapy in treating RA patients who had insufficient response and persistent pain and inflammation in just one or two joints through its down regulating effect on inflammatory cytokines IL1B, TNF α with subsequent improvement of local joint inflammation, disease activity and QL.

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Punicalagin Prevents Inflammation in LPS-Induced RAW264.7 Macrophages by Inhibiting FoxO3a/Autophagy Signaling Pathway

Nutrients ◽

10.3390/nu11112794 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2794 ◽

Cited By ~ 8

Author(s):

Cao ◽

Chen ◽

Ren ◽

Zhang ◽

Tan ◽

...

Keyword(s):

Western Blot ◽

Signaling Pathway ◽

Inflammatory Cytokines ◽

Blot Analysis ◽

Western Blot Analysis ◽

Inflammatory Responses ◽

Raw264.7 Macrophages ◽

Tnf Α ◽

Autophagy Inhibition ◽

Pro Inflammatory Cytokines

Punicalagin, a hydrolysable tannin of pomegranate juice, exhibits multiple biological effects, including inhibiting production of pro-inflammatory cytokines in macrophages. Autophagy, an intracellular self-digestion process, has been recently shown to regulate inflammatory responses. In this study, we investigated the anti-inflammatory potential of punicalagin in lipopolysaccharide (LPS) induced RAW264.7 macrophages and uncovered the underlying mechanisms. Punicalagin significantly attenuated, in a concentration-dependent manner, LPS-induced release of NO and decreased pro-inflammatory cytokines TNF-α and IL-6 release at the highest concentration. We found that punicalagin inhibited NF-κB and MAPK activation in LPS-induced RAW264.7 macrophages. Western blot analysis revealed that punicalagin pre-treatment enhanced LC3II, p62 expression, and decreased Beclin1 expression in LPS-induced macrophages. MDC assays were used to determine the autophagic process and the results worked in concert with Western blot analysis. In addition, our observations indicated that LPS-induced releases of NO, TNF-α, and IL-6 were attenuated by treatment with autophagy inhibitor chloroquine, suggesting that autophagy inhibition participated in anti-inflammatory effect. We also found that punicalagin downregulated FoxO3a expression, resulting in autophagy inhibition. Overall these results suggested that punicalagin played an important role in the attenuation of LPS-induced inflammatory responses in RAW264.7 macrophages and that the mechanisms involved downregulation of the FoxO3a/autophagy signaling pathway.

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AB0827 SERUM NESPHATIN-1 IN PATHOGENESIS RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2503 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1437.2-1438

Author(s):

T. Kvlividze ◽

V. Polyakov ◽

В. Zavodovsky ◽

Y. Polyakova ◽

L. Seewordova ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Blood Serum ◽

Inflammatory Cytokines ◽

Inflammatory Markers ◽

Healthy People ◽

Healthy Individuals ◽

Markers Of Inflammation ◽

High Level ◽

Pro Inflammatory Cytokines

Background:Interest in highly specialized tissue cytokines contributed to the discovery of new biologically active molecules. Nesfatin-1 (NF) - discovered in 2006 as an anorexigenic factor. NF-1 is believed to be involved in the regulation of energy homeostasis by regulating appetite and water intake. The role of NF-1 in the pathogenesis of inflammatory diseases is poorly understood. Recently, studies have found a relationship between an increased level of NF-1 and inflammatory markers in various pathologies.Objectives:Study of the level of nesfatin-1 in the blood serum of healthy people, determination of the correlation between the level of NF-1 with the severity of clinical symptoms and classic markers of inflammation in patients with RA.Methods:120 persons were examined: 90 patients with RA and 30 healthy people. All patients underwent a complete clinical and laboratory examination. Plasma NF-1 levels were determined using commercial test systems (RaiBiotech, cat # EIA-NESF) according to the manufacturer’s instructions. Patients with various forms of RA were comparable in age to the group of healthy individuals. Statistical processing of clinical examination data was carried out using the “STATISTICA 10.0 for Windows” software package. Quantitative data were processed statistically using the parametric Student’s t-test, qualitative data using the non-parametric chi-square test. The significance of differences between groups was determined using analysis of variance. The results were considered statistically significant at p <0.05.Results:The average level of NF-1 in blood serum in healthy individuals was 31.79 ± 3.21 ng / ml (M ± σ). The level of normal NF-1 values in healthy individuals, defined as M ± 2σ, ranged from 25.3 to 37.83 ng / ml. There was no significant difference in the levels of circulating NF-1 and BMI in healthy individuals and patients with RA (p> 0.05). The inverse relationship of a lower level of NF-1 with an increase in BMI was not significant.Group 1 (66 patients with RA) with increased serum NF-1 levels (> 37.83 ng / ml), and group 2 (44 patients) with normal values (<37.83 ng / ml). A high level of NF-1 was characteristic for patients with high activity according to DAS28, RF seropositive, ACCP-positive, with extra-articular manifestations, who had been ill for 10 years or more. A reliable relationship between the level of NF-1 in the blood serum and laboratory parameters of RA activity - ESR, CRP, was shown, and secondary synovitis was more common. Our data show a direct correlation between the NF-1 level of the pro-inflammatory markers of RA.Conclusion:The positive correlation between the level of NF-1 and classical markers of inflammation, such as CRP and ESR, confirms the involvement of NF-1 in the pathophysiology of inflammation in RA. This is also evidenced by the correlation of a high level of NF-1 in the blood serum with a more severe clinical picture of RA. It is known that NF-1 can promote the release of pro-inflammatory cytokines such as interleukin-8 (IL-8), interleukin-6 (IL-6), and macrophage inflammatory protein-1a (MIP-1a) in the chondrocytes of RA patients.It is necessary to further study the role of NF-1 in the pathogenesis of systemic inflammatory reactions and the possibility of targeting pro-inflammatory cytokines, the possibility of regulating the level of NF-1 by drugs.References:[1]Kvlividze T.Z., Zavodovsky B.V., Akhverdyan Yu.R. Kvlividze T.Z., Zavodovsky B.V., Akhverdyan Yu.R., Polyakova Yu.V., Sivordova L.E., Yakovlev A.T., Zborovskaya I.A. Serum nesfatin -1 as a marker of systemic inflammation in rheumatoid arthritis. Klinicheskaya Laboratornaya Diagnostika (Russian Clinical Laboratory Diagnostics). 2019; 64 (1): 53-56 (in Russ.).Disclosure of Interests:None declared

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