Pro-inflammatory Cytokine In Rheumatoid Arthritis Research Articles

Exercise as Medicine in Rheumatoid Arthritis: Effects on Function, Body Composition, and Cardiovascular Disease Risk

Rheumatoid arthritis (RA) is characterised by functional disability and inflammation. This review explores the beneficial effects of exercise on function and cardiovascular disease risk in RA and explores the possibility that some of these beneficial effects may be moderated via exercise-induced improvements in body composition.

OP0106 The Impact of Pro-Inflammatory Cytokines on the Expression and Function of Long Noncoding RNA (LNCRNA) in Rheumatoid Arthritis Synovial Fibroblasts

BackgroundLong noncoding RNA (lncRNA) have emerged as key regulators of gene expression. Recently, new susceptibility loci were identified for severity of rheumatoid arthritis (RA), mapping to different lncRNA genes (Knevel...

B cell activating factor-dependent expression of vascular endothelial growth factor in MH7A human synoviocytes stimulated with tumor necrosis factor-α

Angiogenesis in rheumatoid arthritis (RA) is one of the histological hallmarks, which is mediated by expression of vascular endothelial growth factor (VEGF) in RA synovium. VEGF expression is enhanced by TNF-α, the main pro-inflammatory cytokine in RA. B cell activating factor (BAFF) which plays a role in maturation and maintenance of B cells is also associated with autoimmune RA. Here, we investigated whether BAFF could regulate VEGF expression in TNF-α-stimulated synovium using MH7A synovial cells that are established by transfection with the SV40 T antigen. Changes in hBAFF and hVEGF were measured by western blotting, RT-PCR and luciferase promoter assay. When MH7A cells were treated with TNF-α, we observed that TNF-α increased the expression of hBAFF and hVEGF. TNF-α also increased transcriptional activity of hBAFF and hVEGF as judged by luciferase promoter assay. Inhibition of hBAFF expression with BAFF-siRNA decreased transcriptional level and activity of hVEGF. In addition, when c-fos expression was inhibited by the transfection of MH7A cells with c-fos-siRNA, data showed that transcriptional level and activity of both hBAFF and hVEGF were attenuated by the activation with TNF-α. Our results demonstrate for the first time that VEGF-mediated angiogenesis in RA could be controlled by TNF-α-induced BAFF expression through c-Fos. Data suggest that TNF-α-induced BAFF expression and BAFF-mediated VEGF expression in synovium may cooperate to maintain the capacity of such cells to protect B cells from apoptosis and the supply of nutrients and oxygen in inflammatory microenvironments.

Efficacy and safety of tocilizumab in rheumatoid arthritis

BackgroundA novel target for the treatment of rheumatoid arthritis (RA) is cytokine interleukin-6 (IL-6), a key pro-inflammatory cytokine in RA contributing to both the articular and systemic manifestations of the...

Infections in patients with rheumatoid arthritis receiving anti-cytokine therapy: biological mechanisms and clinical aspects

Different animal studies show that several proinflammatory cytokines are essential for natural resistance to specific infections, particularly versus intracellular organisms. However, uncontrolled overproduction of some proinflammatory cytokines, in diseases such as rheumatoid arthritis, can be just as dangerous to the host as the absence of the same cytokines. Reduction in the production and/or activities of proinflammatory cytokines in rheumatoid arthritis remains a therapeutic objective for many patients. The tumour necrosis factor-alpha (TNF-alpha) blockers infliximab, etanercept and adalimumab and the recombinant interleukin 1 (IL-1) receptor antagonist anakinra are effective in patients with active rheumatoid arthritis. However, there is a growing body of clinical evidence that neutralization of TNF-alpha is associated with an increased risk of opportunistic infections, including mycobacterial diseases. Blockade of IL-1 activity with the IL-1 receptor antagonist (IL-1Ra) appears, at present, to be relatively safe. Postmarketing experience and pharmacovigilance programs are necessary to determine the overall safety profile of the new agents. At this time, treating physicians must weigh carefully the benefits of biologics against their safety, particularly in patients at risk of infection.

High mobility group box 1 potentiates the pro-inflammatory effects of interleukin-1β in osteoarthritic synoviocytes

IntroductionHigh mobility group box 1 (HMGB1) is released by necrotic cells or secreted in response to inflammatory stimuli. Extracellular HMGB1 may act as a pro-inflammatory cytokine in rheumatoid arthritis. We have recently reported that HMGB1 is released by osteoarthritic synoviocytes after activation with interleukin-1beta (IL-1β) The present study investigated the role of HMGB1 in synovial inflammation in osteoarthritis (OA).MethodsHMGB1 was determined in human synovium using immunohistochemistry, comparing normal to OA. OA synoviocytes were incubated with HMGB1 at 15 or 25 ng/ml in the absence or presence of IL-1β (10 ng/ml). Gene expression was analyzed by quantitative PCR and protein expression by Western Blot and ELISA. Matrix metalloproteinase (MMP) activity was studied by fluorometric procedures and nuclear factor (NF)-κB activation by transient transfection with a NF-κB-luciferase plasmid.ResultsIn the normal synovium, HMGB1 was found in the synovial lining cells, sublining cells, and in the vascular wall cells. The distribution of HMGB1 in OA synovium was similar but the number of HMGB1 positive cells was higher and HMGB1 was also present in infiltrated cells. In normal synovial membrane cells, HMGB1 was found mostly in the nuclei, whereas in OA, HMGB1 was generally found mostly in the cytoplasm. In OA synoviocytes, HMGB1 alone at concentrations of 15 or 25 ng/ml did not affect the production of IL-6, IL-8, CCL2, CCL20, MMP-1 or MMP-3, but in the presence of IL-1β, a significant potentiation of protein and mRNA expression, as well as MMP activity was observed. HMGB1 also enhanced the phosphorylated ERK1/2 and p38 levels, with a lower effect on phosphorylated Akt. In contrast, JNK1/2 phosphorylation was not affected. In addition, HMGB1 at 25 ng/ml significantly potentiated NF-κB activation in the presence of IL-1β.ConclusionsOur results indicate that HMGB1 is overexpressed in OA synovium and mostly present in extracellular form. In OA synoviocytes, HMGB1 cooperates with IL-1β to amplify the inflammatory response leading to the production of a number of cytokines, chemokines and MMPs. Our data support a pro-inflammatory role for this protein contributing to synovitis and articular destruction in OA.

Outside‐to‐inside signaling through transmembrane tumor necrosis factor reverses pathologic interleukin‐1β production and deficient apoptosis of rheumatoid arthritis monocytes

Monocytes are a major source of proinflammatory cytokines in rheumatoid arthritis (RA), and inhibitors of monocytic cytokines are highly efficient agents for treatment of the disease. The aim of this study was to analyze the effects of a therapeutic anti-tumor necrosis factor alpha (anti-TNFalpha) antibody on monocytes from patients with RA and healthy control subjects. Peripheral blood monocytes from patients with RA and healthy control subjects were incubated in the presence of anti-TNFalpha antibody or IgG. Annexin V staining, caspase activation, poly(ADP-ribose) polymerase cleavage, and DNA staining with propidium iodide were used to analyze apoptosis. The signaling events elicited in monocytes by infliximab were analyzed by Western blotting and electromobility shift assay. Peripheral blood monocytes from patients with RA were characterized by increased expression of transmembrane TNFalpha, spontaneous in vitro production of interleukin-1beta (IL-1beta), and a decreased rate of spontaneous ex vivo apoptosis. Incubation with infliximab induced significantly increased apoptosis in monocytes from patients with RA but not in monocytes from healthy control subjects. This apoptosis was triggered by reverse signaling of transmembrane TNF after ligation by infliximab and was independent of caspase activation. Instead, transmembrane TNF reverse signaling inhibited the constitutive NF-kappaB activation in RA monocytes, suppressed IL-1beta secretion, and normalized spontaneous in vitro apoptosis. This normalization was reversible by the addition of exogenous IL-1beta. This study demonstrates that outside-to-inside signaling through transmembrane TNF after ligation by infliximab inhibits constitutive NF-kappaB activation and suppresses spontaneous IL-1beta production by monocytes from patients with RA. Besides the induction of monocyte apoptosis, this inhibition could also contribute to the therapeutic effects observed during treatment with TNFalpha inhibitors.

Upregulation of Macrophage Migration Inhibitory Factor (MIF) Production by Engagement of Toll-like Receptor 3 (TLR3) on Fibroblast-like Synoviocyte (FLS) from Patients with Rheumatoid Arthritis

Objective: Rheumatoid arthritis (RA) is a chronic autoimmune disease. Macrophage migration inhibitory factor (MIF) has been shown to be an important pro-inflammatory cytokine in RA. The aim of this study was to determine if the engagement of toll-like receptor 3 (TLR3) induces the production of MIF in the fibroblast-like synoviocytes (FLS) of patients with RA. Methods: The expression of inflammatory cytokines (e.g. MIF, IL-6, IL-1β and TNFα) and toll-like receptors (e.g. TLR2, TLR3 and TLR4) in the synovial tissue were quantified by immunohistochemistry. FLS were isolated from the synovial tissues of patients with RA and stimulated with TLR-3 ligand polyI:C, in the presence of a neutralizing antibody against IL-6. The concentrations of MIF and IL-6 in the culture supernatants from the FLS were measured using sandwich ELISA. Results: The engagement of TLR3 with PolyI:C increased the production of MIF in FLS. The stimulatory effect of these TLR ligands showed a dose-dependent trend. The combination of

Effector mechanisms of interleukin-17 in collagen-induced arthritis in the absence of interferon-γ and counteraction by interferon-γ

IntroductionInterleukin (IL)-17 is a pro-inflammatory cytokine in rheumatoid arthritis (RA) and collagen-induced arthritis (CIA). Since interferon (IFN)-γ inhibits Th17 cell development, IFN-γ receptor knockout (IFN-γR KO) mice develop CIA more readily. We took advantage of this model to analyse the mechanisms of action of IL-17 in arthritis. The role of IFN-γ on the effector mechanisms of IL-17 in an in vitro system was also investigated.MethodsIFN-γR KO mice induced for CIA were treated with anti-IL-17 or control antibody. The collagen type II (CII)-specific humoral and cellular autoimmune responses, myelopoiesis, osteoclastogenesis, and systemic cytokine production were determined. Mouse embryo fibroblasts (MEF) were stimulated with IL-17, tumor necrosis factor (TNF)-α and the expression of cytokines and chemokines were determined.ResultsA preventive anti-IL-17 antibody treatment inhibited CIA in IFNγR KO mice. In the joints of anti-IL-17-treated mice, neutrophil influx and bone destruction were absent. Treatment reduced the cellular autoimmune response as well as the splenic expansion of CD11b+ cells, and production of myelopoietic cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-6. IL-17 and TNF-α synergistically induced granulocyte chemotactic protein-2 (GCP-2), IL-6 and receptor activator of NFκB ligand (RANKL) in MEF. This induction was profoundly inhibited by IFN-γ in a STAT-1 (signal transducer and activator of transcription-1)-dependent way.ConclusionsIn the absence of IFN-γ, IL-17 mediates its pro-inflammatory effects mainly through stimulatory effects on granulopoiesis, neutrophil infiltration and bone destruction. In vitro IFN-γ profoundly inhibits the effector function of IL-17. Thus, aside from the well-known inhibition of the development of Th17 cells by IFN-γ, this may be an additional mechanism through which IFN-γ attenuates autoimmune diseases.

Melanoma inhibitory activity, a biomarker related to chondrocyte anabolism, is reversibly suppressed by proinflammatory cytokines in rheumatoid arthritis

Objective:In mice, melanoma inhibitory activity (MIA) is a chondrocyte-specific molecule with similar regulation to collagen type II. As MIA is a small secreted protein, its value as cartilage biomarker in...

Cytokine as New Rheumatoid Arthritis Target

Rheumatoid arthritis is a debilitating autoimmune disease characterized by inflammation of the joints that affects millions of people. Joosten et al. report that a recently characterized cytokine, interleukin-32 (IL-32), appears to have an important role in the human disease. Tissue samples from patients with rheumatoid arthritis showed increased expression of IL-32 compared with that in control samples. The abundance of IL-32 correlated with markers of inflammation. Injection of human IL-32 into the knee joint of C57/B16 mice caused swelling and influx of inflammatory cells. IL-32 can induce expression of tumor necrosis factor-α (TNF-α) in cultured cells, and TNF-α is a major contributor to chronic joint inflammation. IL-32 appeared to exert its inflammatory effects through TNF-α, because injection of IL-32 failed to cause swelling of joints in TNF-α knockout mice. Together, the results from human patients and animal studies lead the authors to conclude that elucidation of mechanisms to reduce activity of IL-32 provides a new strategy for development of therapies that may benefit patients suffering from rheumatoid arthritis. L. A. B. Joosten, M. G. Netea, S.-H. Kim, D.-Y. Yoon, B. Oppers-Walgreen, T. R. D. Radstake, P. Barrera, F. A. J. van de Loo, C. A. Dinarello, W. B. van den Berg, IL-32, a proinflammatory cytokine in rheumatoid arthritis. Proc. Natl. Acad. Sci. U.S.A. 103 , 3298-3303 (2006). [Abstract] [Full Text]

Infliximab for rheumatoid arthritis

There is accumulating evidence that early and aggressive treatment of rheumatoid arthritis may lead to enhanced and sustained clinical outcomes. The goal of therapy in rheumatoid arthritis is remission. Tumor necrosis factor is a pivotal pro-inflammatory cytokine in rheumatoid arthritis. Infliximab, a chimeric murine human antitumor necrosis factor monoclonal antibody, was the first tumor necrosis factor blocking agent to be used in humans. Blockade of tumor necrosis factor occupies a central hierarchal role in the treatment of rheumatoid arthritis and now several other chronic inflammatory conditions. Although there are still many limitations and hurdles in the management of rheumatoid arthritis, the introduction of infliximab and related drugs into clinical practice represents a real therapeutic advance which has made remission an achievable goal for many more patients. This article describes the role of tumor necrosis factor and the impact of its blockade with infliximab in rheumatoid arthritis.

Effects of repeated infliximab therapy on serum lipid profile in patients with refractory rheumatoid arthritis

Background Patients with rheumatoid arthritis (RA) frequently display an atherogenic lipid profile which has been linked with inflammation. Tumor necrosis factor-α (TNF-α), a pivotal pro-inflammatory cytokine in RA may be involved in the development of the disturbed lipid metabolism. We investigated whether infliximab, an anti-TNF-α therapy, may modify the lipid profile. Methods 56 consecutive RA patients were treated with infliximab (3 mg/kg at weeks 0, 2, 6, 14, 22, 30). Lipid profile and CRP were assayed at baseline and before infusion at weeks 6 and 30. Baseline values were compared with those in 56 healthy volunteers. Results At baseline, the concentrations of HDL-cholesterol were lower in RA patients than in the controls (1.3 ± 0.4 vs. 1.5 ± 0.2 mmol/L; p < 0.01). The triglyceride concentrations (1.6 ± 0.8 vs. 1.3 ± 0.4 mmol/L, p < 0.01), the ratio of total cholesterol / HDL-cholesterol (4.3 ± 1.6 vs. 3.2 ± 0.5, p < 0.001) and LDL-cholesterol / HDL-cholesterol (2.6 ± 1.2 vs. 1.7 ± 0.5, p < 0.001) were significantly higher in RA patients than in controls. After 6 weeks of infliximab therapy, the mean total cholesterol concentration increased by 25% ( p < 0.001), LDL-cholesterol by 24% ( p < 0.001) and HDL-cholesterol by 30% ( p < 0.001). The decrease in CRP levels to 30 week inversely correlated with the increase in HDL-cholesterol ( r = − 0.47, p = 0.005). Conclusions Infliximab administration is associated with important increases in cholesterol levels in all its forms but as no significant beneficial effect on the atherogenic ratio.

Association of interleukin-18 expression with enhanced levels of both interleukin-1beta and tumor necrosis factor alpha in knee synovial tissue of patients with rheumatoid arthritis.

To examine the expression patterns of interkeukin-18 (IL-18) in synovial biopsy tissue of patients with rheumatoid arthritis (RA), and to determine whether expression of this primary cytokine is related to the expression of other cytokines and adhesion molecules and related to the degree of joint inflammation. Biopsy specimens of knee synovial tissue either without synovitis (n = 6) or with moderate or severe synovitis (n = 11 and n = 12, respectively) were obtained from 29 patients with active RA. Paraffin-embedded, snap-frozen sections were used for immunohistochemical detection of IL-18, tumor necrosis factor alpha (TNFalpha), IL-1beta, IL-12, and IL-17. Furthermore, adhesion molecules, such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin, and cell markers CD3, CD14, and CD68 were stained. IL-18 staining was detectable in 80% of the RA patients, in both the lining and sublining of the knee synovial tissue. IL-18 expression in the synovial tissue was strongly correlated with the expression of IL-1beta (in the sublining r = 0.72, in the lining r = 0.71; both P < 0.0001) and TNFalpha (in the sublining r = 0.59, P < 0.0007, and in the lining r = 0.68, P < 0.0001). In addition, IL-18 expression in the sublining correlated with macrophage infiltration (r = 0.64, P < 0.0007) and microscopic inflammation scores (r = 0.78, P < 0.0001), and with the acute-phase reaction as measured by the erythrocyte sedimentation rate (r = 0.61, P < 0.0004). Interestingly, RA synovial tissue that coexpressed IL-18 and IL-12 demonstrated enhanced levels of the Th1-associated cytokine IL-17. Our results show that expression of IL-18 is associated with that of IL-1beta and TNFalpha and with local inflammation in the synovial tissue of patients with RA. In addition, synovial IL-18 expression correlates with the acute-phase response. These data indicate that IL-18 is a primary proinflammatory cytokine in RA that drives the local production of IL-1beta and TNFalpha.

Role of cytokines in rheumatoid arthritis

Cytokines have emerged as crucial players in mediating synovial inflammation in the rheumatoid joint, where the local and systemic production of cytokines appears to account for most of the pathologic and clinical manifestations of rheumatoid arthritis. Among the cytokines, tumor necrosis factor-alpha and interleukin-1 are considered to be of great importance in the pathogenesis of the disease. Other pro-inflammatory cytokines in rheumatoid arthritis are interleukin-6, interleukin-8, leukemia inhibitory factor, granulocyte-macrophage colony-stimulating factor and transforming growth factor-beta The potent antiinflammatory cytokines interleukin-4 and interleukin-10, which are powerful inhibitors of most of these mediators, seem to be promising agents and candidates for an optimal approach to treatment.