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ID PMID Title PublicationDate abstract
10364900 Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 1999 Apr OBJECTIVES: To investigate the potential clinical benefit of a combination therapy. METHODS: 205 patients fulfilling the ACR criteria for rheumatoid arthritis (RA), not treated with disease modifying antirheumatoid drugs previously, with an early (< or = 1 year duration), active (Disease Activity Score (DAS) > 3.0), rheumatoid factor and/or HLA DR 1/4 positive disease were randomised between sulphasalazine (SASP) 2000 (maximum 3000) mg daily (n = 68), or methotrexate (MTX) 7.5 (maximum 15) mg weekly (n = 69) or the combination (SASP + MTX) of both (n = 68). RESULTS: The mean changes in the DAS during the one year follow up of the study was -1.15, -0.87, -1.26 in the SASP, MTX, and SASP + MTX group respectively (p = 0.019). However, there was no statistically significant difference in terms of either EULAR good responders 34%, 38%, 38% or ACR criteria responders 59%, 59%, 65% in the SASP, MTX, and SASP + MTX group respectively. Radiological progression evaluated by the modified Sharp score was very modest in the three groups: mean changes in erosion score: +2.4, +2.4, +1.9, in narrowing score: +2.3, +2.1, +1.6 and in total damage score: +4.6, +4.5, +3.5, in the SASP, MTX, and SASP + MTX groups respectively. Adverse events occurred more frequently in the SASP + MTX group 91% versus 75% in the SASP and MTX group (p = 0.025). Nausea was the most frequent side effect: 32%, 23%, 49% in the SASP, MTX, and SASP + MTX groups respectively (p = 0.007). CONCLUSION: This study suggests that an early initiation therapy of disease modifying drug seems to be of benefit. However, this study was unable to demonstrate a clinically relevant superiority of the combination therapy although several outcomes were in favour of this observation. The tolerability of the three treatment modalities seems acceptable.
10555883 The engineered human anti-tumor necrosis factor-alpha antibody CDP571 inhibits inflammator 1999 Nov OBJECTIVE: We investigated the effect of an engineered human anti-tumor necrosis factor-alpha antibody, CDP571, on immune functions as well as bone and cartilage turnover in patients with rheumatoid arthritis (RA) in a placebo controlled trial. We also assessed the effects of repeated treatment with CDP571 in an open label continuation study. METHOD: Thirty-six patients were treated with either placebo or 0.1, 1, or 10 mg/kg of CDP571 given as an intravenous infusion. The followup period was 8 weeks. Lymphocyte phenotype, soluble CD4 (sCD4), soluble interleukin 2 receptor (sIL-2R), IL-6, and stromelysin levels in the blood were measured before and after treatment; bone and cartilage markers (pyridinoline, deoxypyridinoline, N-terminal telopeptide) were similarly assessed in the urine. Patients who completed a placebo controlled trial of CDP571 were offered further treatment with CDP571. They received a maximum of 2 further doses of 1 mg/kg (7 patients) or 10 mg/kg (9 patients) in an open study. RESULTS: Plasma IL-6 level was statistically significantly reduced in the 1 and 10 mg/kg groups. In the 10 mg/kg group, there were also reductions in plasma stromelysin and urine bone markers, although there was no change in sCD4 and sIL-2R levels. Repeat doses of CDP571 were well tolerated and continued to suppress the acute phase response and disease activity. CONCLUSION: Treatment with 10 mg/kg of CDP571 reduced IL-6 and surrogate markers of bone turnover in RA, suggesting that CDP571 might prevent joint damage in RA. Since there was no effect on lymphocyte markers despite the marked reduction in inflammation, CDP571 appears to have no effect on ongoing CD4 T cell activation.
9227325 Inhibitory effects of interleukin-10 on synovial cells of rheumatoid arthritis. 1997 Jun This paper describes the immunoregulatory effects of interleukin-10 (IL-10) on synovial cells in vitro. Synovial cells were cultured with IL-10 in the presence or absence of various cytokines. Following incubation, the costimulatory molecule expression on synovial cells and cytokine production in culture supernatants were analysed by an indirect immunofluorescence method and enzyme-linked immunosorbent assay, respectively. We also examined the effect of IL-10 on the function of synovial cells as antigen-presenting cells (APC). Synovial cells spontaneously express several kinds of costimulatory molecule and produce various kinds of cytokines. Stimulation of synovial cells with interferon-gamma (IFN-gamma), IL-1 beta, or 12-O-tetradecanoyl phorbol 13-acetate (TPA) markedly enhanced the expression of costimulatory molecules and cytokine production of these cells. Both spontaneous and up-regulated costimulatory molecule expression and cytokine production were significantly suppressed by the addition of IL-10. Autologous T-cell proliferation was stimulated by purified protein derivative (PPD) in IFN-gamma-treated synovial cells and treatment of these synovial cells with IL-10 also suppressed T-cell proliferation. Our results suggest that IL-10 has an inhibitory effect on synovial cells and is an important immunoregulatory component of the cytokine network in rheumatoid arthritis.
12905876 [Gene clone of autoantigen hnRNP A2/B1 and research on expression in synovium]. 2001 Oct OBJECTIVE: To investigate hnRNPA2/B1's role in rheumatoid synovitis by obtaining its cDNA sequence and analyzing its expression in synovium. METHODS: Total RNA was isolated from peripheral blood mononuclear cells (PBMC) and the RT-PCR was performed. The fragment was cloned into PUC-T1 plasmids and further sequenced. We detected it's expression in synovium with monoclonal antibodies and specific cDNA probes by immunohistochemistry and in situ hybridization. RESULTS: The fragment was identified by DNA sequencing. The expression in rheumatoid synovium was higher than that from osteoarthritis and the normal controls (P < 0.05). CONCLUSION: hnRNP A2/B1 cDNA has been cloned successfully and hnRNP A2/B1 might play an important role in rheumatoid synovitis.
10323451 C-myc antisense oligodeoxynucleotides can induce apoptosis and down-regulate Fas expressio 1999 May OBJECTIVE: To investigate the role of c-myc in the pathogenesis of rheumatoid arthritis (RA) and the mechanism of synovial apoptosis. METHODS: Using cultured human synoviocytes from patients with RA and c-myc antisense oligodeoxynucleotides (AS ODN), we examined the inhibition of cell proliferation by the MTT assay and the induction of apoptosis with TUNEL staining and fluorescence microscopy. In addition, the effect of c-myc on down-regulation of Fas expression was analyzed by flow cytometry, cytotoxicity assay, and reverse transcriptase-polymerase chain reaction. RESULTS: Treatment with c-myc AS ODN induced inhibition of cell proliferation, along with down-regulation of c-Myc protein and c-myc messenger RNA (mRNA) expression. The morphologic changes of synovial cell death were typical of apoptosis. In addition, c-myc AS ODN treatment down-regulated expression of Fas mRNA but not Fas antigen. Analysis of the involvement of the caspase cascade revealed that the cytotoxic activity of c-myc AS ODN was completely blocked by inhibitors of both caspase 1 (YVAD-FMK) and caspase 3 (DEVD-FMK). CONCLUSION: Our results strongly suggest that c-myc AS ODN might be a useful therapeutic tool in RA and clarify that cell death by c-myc AS ODN is induced through the caspase cascade, similar to Fas-induced apoptosis. In addition, combination therapy with anti-Fas antibody and c-myc AS ODN reduced Fas-dependent cytotoxicity.
10419867 Soluble urokinase plasminogen activator receptor in plasma of patients with inflammatory r 1999 Aug OBJECTIVE: Urokinase type plasminogen activator (uPA) catalyses the formation of the proteolytic enzyme plasmin, which is involved in matrix degradation in the processes of tissue remodelling. Because of a surface bound uPA receptor (uPAR), expressed by some cell types (for example, macrophages, malignant cells and inflammatory activated synoviocytes), the action of uPA can be localised and intensified. uPAR seems to have a role in the mechanisms leading to invasive growth of malignant tissue and the rheumatoid pannus. uPAR may become cleaved at its cell surface anchor, thus forming a free soluble receptor (suPAR). suPAR is detectable in low but constant values in plasma of healthy people, while increased concentrations are found in patients with disseminated malignant disease, so that suPAR may be an indicator of invasive growth and tissue remodelling. suPAR concentrations in plasma have not previously been measured in rheumatic patients. A controlled cross sectional measurement was performed of suPAR in plasma of patients with various inflammatory rheumatic disorders with special reference to rheumatoid arthritis (RA). METHODS: suPAR in plasma was measured by ELISA technique in patients with RA (n=51), reactive arthritis (ReA) (n=23), primary Sjögren's syndrome (PSS) (n=42) and sex and age matched healthy controls (n=53). RESULTS: In the control group suPAR (median) was 0. 91 (range 0.56-1.94) microg/l. Median suPAR value in RA was 1.47 (range 0.65-6.62) microgram/l; in ReA 0.68 microgram/l (range 0.52-1.48) and in PSS 1.12 microgram/l (range 0.76-1.92); p versus controls <0.001 in all patient groups. suPAR values in RA were also significantly increased compared with ReA (p<0.001) and PSS (p=0.004) groups. suPAR in RA was positively correlated to C reactive protein (CRP) (p<0.01) and erythrocyte sedimentation rate (p<0.05) and number of swollen joints (p<0.05). The ReA group had the highest CRP values of all groups, but at the same time the lowest suPAR concentrations in plasma. CONCLUSIONS: Increased suPAR concentrations were found in plasma in RA, and to a smaller extent also in PSS, but not in ReA. In RA suPAR is related to disease activity. suPAR seems though not merely to be an acute phase reactant like CRP. Increased suPAR values might reflect erosive activity in RA.
10693864 Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiati 2000 Feb OBJECTIVE: To clarify the mechanism by which osteoclasts are formed in culture of rheumatoid synoviocytes by exploring the involvement of receptor activator of nuclear factor kappaB ligand (RANKL)/osteoclast differentiation factor (ODF). METHODS: Osteoclast formation was evaluated in cocultures of rheumatoid synovial fibroblasts and peripheral blood mononuclear cells (PBMC) in the presence of macrophage colony stimulating factor and 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) utilizing separating membrane filters. RANKL/ODF expression was examined by Northern blotting in synovial tissues from 5 rheumatoid arthritis (RA) patients and tissues from patients with giant cell tumor (GCT), osteosarcoma (OS), and osteoarthritis (OA). RANKL/ODF expression and the ability of synovial fibroblasts to support osteoclastogenesis were investigated in coculture with PBMC in the presence or absence of 1,25(OH)2D3, and soluble RANKL/ODF and osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) were measured by enzyme-linked immunosorbent assay. The effects of OPG/OCIF on the osteoclastogenesis in the primary culture of rheumatoid synoviocytes and the coculture system were determined. RESULTS: Synovial fibroblasts did not induce osteoclastogenesis when separately cocultured with PBMC. Northern blotting revealed that RANKL/ODF was highly expressed in all tissues from RA and GCT patients, but not from OA or OS patients. Cultured rheumatoid synovial fibroblasts efficiently induced osteoclastogenesis in the presence of 1,25(OH)2D3, which was accompanied by up-regulated expression of RANKL/ODF and decreased production of OPG/OCIF. Osteoclastogenesis from synoviocytes was dose-dependently inhibited by OPG/OCIF. CONCLUSION: RANKL/ODF expressed on synovial fibroblasts is involved in rheumatoid bone destruction by inducing osteoclastogenesis and would therefore be a good therapeutic target.
9893571 Hyaluronan production in human rheumatoid fibroblastic synovial lining cells is increased 1998 Oct OBJECTIVES: To investigate the regulatory roles of interleukin 1 beta (IL1 beta), tumour necrosis factor alpha (TNF alpha), interferon gamma (IFN gamma) or transforming growth factor beta 1 (TGF beta 1) on hyaluronan (HA) synthesis by human fibroblastic synovial lining cells. METHODS: Concentrations of HA in culture supernatants of fibroblastic synovial lining cell line (RAMAK-1 cell line) with or without stimulation by IL1 beta, TNF alpha, IFN gamma or TGF beta 1 were measured by sandwich binding protein assay. Levels of HA synthase mRNA of the cells with or without stimulation were detected by reverse transcribed polymerase chain reaction. Molecular weights of HA in the culture supernatants of the cells with or without stimulation were measured using high performance gel permeation liquid chromatography. RESULTS: HA synthesis by the cells was not significantly augmented by TNF alpha or by IFN gamma. It was significantly stimulated by IL1 beta but inhibited by TGF beta 1. Molecular weights of HA in the culture supernatants of the cells were unchanged by stimulation with TNF alpha. They were remarkably increased by stimulation with IL1 beta and IFN gamma, but reduced with TGF beta 1. CONCLUSION: IL 1 beta is an up regulator of HA synthesis, while TGF beta 1 is a down regulator. HA production in the synovial lining cells of inflamed joints (for example, rheumatoid arthritis) might be regulated by the balance of these cytokines.
10224866 [The role of MHC class II genes in the etiopathogenesis of rheumatoid arthritis]. 1998 Rheumatoid arthritis (RA) is associated with HLA-DR4 and DR1 antigens. HLA-DRB1 gene sequences analysis demonstrated that only a limited set of alleles is positively associated with RA. Third hypervariable region sequences (70-74, 86) Q(R)R(K)RAA, G(V) are found in up to 95% of erosive RA. The presence of disease-associated allels may predict severe outcome of the disease. Therefore, their presence may allow us to start aggressive therapy in early stage of the disease.
10084099 The use of combined suprascapular and circumflex (articular branches) nerve blocks in the 1999 Jan Sixteen patients suffering from rheumatoid or osteoarthritis of the shoulder joint were studied. All patients complained of pain and limitation of active movement of the shoulder joint. Combined neural blockade of the suprascapular nerve (SSNB) and articular branches of the circumflex nerve (ACNB) was carried out using 4 mL of 1% prilocaine and 4 mL of 6% aqueous phenol. Following this procedure, the mean value for pain intensity decreased by 69% (VASP 2.7) and for abduction, adduction and flexion increased by 36-67% over a mean time of 13 weeks. Functional external and internal rotation of the shoulder joint also increased after neural blockade. These findings were significant (P < 0.05). Further clinical evaluation of combined SSNB and ACNB in relation to previously reported methods of neural blockade of the shoulder joint is warranted using a randomized, controlled, comparative study. Conventional power calculations (80% power, 5% test) indicate that 17 patients per group would be necessary to detect one standard deviation (about 2 VASP) or 64 per group to detect a change of 0.5 standard deviations.
9408281 Haemarthros induced articular cartilage degradation. 1997 The statement that blood in the articular cavity is cause of cartilage degradation is widely accepted as an axiom. Although the causes of the different articular diseases were explained in numerous studies, none of them has clarified the pathomechanism of haemarthrosis. Our aims were: 1/ to give a morphological description of the blood induced changes in the cartilage, 2/ to verify that the haemarthros is the cause of the cartilage degradation. 10 white rabbits were used in our experimental model. Artificial haemarthros was produced in their left hind knees by intraarticular injection of their own blood. The right hind served as control. The rabbits were divided into to five groups based on the time of the haemarthros (22-50 days). Samples of the condylar cartilage were taken for light, polarization, transmission and scanning electron microscopy examinations. Signs of the disorganization of the matrix structure were showed by polarisation microscope and serious lesions were detected in the perichondrium by scanning electron microscope. Similarity have been suggested amongst the pathomechanism of haemarthrosis and other degenerative cartilage diseases (e. g.: osteoarthrosis, rheumatoid arthritis), so we made the same comparison. In many cases similar morphological changes were observed, as described by other authors in case of degenerative diseases.
9375883 Association of factor V Leiden with Behçet's disease. 1997 Nov OBJECTIVE: Studies show an association between factor V Leiden and venous thrombosis. Since venous thrombosis is common in Behçet's disease (BD), we looked for an association between thrombosis in BD and the presence of factor V Leiden. METHODS: Twenty-three patients with BD according to International Study Group criteria and 22 patients with rheumatoid arthritis by American College of Rheumatology criteria as controls participated in the study. Patients with BD and controls were tested for the presence of factor V Leiden by polymerase chain reaction (PCR) amplification of genomic DNA and by restriction enzymatic analysis of PCR products. RESULTS: Three of 23 patients with BD were positive for factor V Leiden (13%). Among BD patients without thrombosis 0/15 were positive; among those with thrombosis 3 of 8 were positive (37.5%) for factor V. Only one patient with RA was positive for factor V Leiden. CONCLUSION. The presence of factor V Leiden in patients with BD may markedly increase the risk of thrombosis.
10743830 Reversible methotrexate associated lymphoproliferative disease evolving into Hodgkin's dis 2000 Mar We describe a case of nodular sclerosing Hodgkin's disease (NSHD) developing in a 61-year-old woman with seropositive rheumatoid arthritis treated with oral methotrexate (MTX) 5 to 15 mg/week for 5 years. Computed tomography (CT) of the abdomen revealed splenomegaly and marked abdominal and retroperitoneal lymphadenopathy. MTX was discontinued; several weeks later prednisone 10 mg/day was added to control worsening polyarthralgia. Repeat CT at 3 months showed almost complete regression of the splenomegaly and lymphadenopathy. However, CT studies at 10 months showed asymptomatic progression of lymphadenopathy, which on biopsy revealed NSHD. Patients with apparently reversible MTX associated lymphoproliferative disorder require periodic monitoring for asymptomatic development of malignant lymphoma.
9430695 Arthritis-related B cell epitopes in collagen II are conformation-dependent and sterically 1998 Jan 16 In collagen-induced arthritis, a murine autoimmune model for rheumatoid arthritis, immunization with native but not heat-denatured cartilage-specific collagen type II (CII) induces a B cell response that largely contributes to arthritogenicity. Previously, we have shown that monoclonal antibodies established from arthritis prone DBA/1 mice require the triple-helical conformation of their epitopes for antigen recognition. Here, we present a novel approach to characterize arthritis-related conformational epitopes by preparing a panel of 130 chimeric collagen X/CII molecules. The insertion of a series of CII cassettes into the triple-helical recombinant collagen X allowed for the first time the identification of five triple-helical immunodominant domains of 5-11 amino acid length, to which 75% of 36 monoclonal antibodies bound. A consensus motif, "R G hydrophobic," was found in all immunodominant epitopes. The antibodies were encoded by a certain combination of V-genes in germline configuration, indicating a role of the consensus motif in V-gene selection. The immunodominant domains are spread over the entire monomeric CII molecule with no apparent order; however, a highly organized arrangement became apparent when the CII molecules were displayed in the quarter-staggered assembly within a fibril. This discrete epitope organization most likely reflects structural constraints that restrict the exposure of CII epitopes on the surface of heterotypically assembled cartilage fibrils. Thus, our data suggest a preimmune B cell selection process that is biased by the accessibility of CII determinants in the intact cartilage tissue.
11557649 Comorbidity and lifestyle, reproductive factors, and environmental exposures associated wi 2001 Oct OBJECTIVE: To evaluate the influence of lifestyle, reproduction, and some external factors on the development of rheumatoid arthritis (RA) and to describe its comorbidity. METHODS: Cases were identified retrospectively from 1980 to 1995 at the University Hospital in Linköping, Sweden. The study comprised 422 cases and 859 randomly selected population referents. Data on possible aetiological factors and comorbidity were collected by postal questionnaire. RESULTS: The response rates were 67% among cases and 59% among referents. A decrease in the occurrence of atopic allergy was seen in the cases (odds ratio (OR) 0.6, 95% confidence interval (CI) 0.4 to 1.0). There was a positive association between RA and insulin treatment (OR 10.2, 95% CI 1.7 to 60.8) in women, and women with a short fertile period had an increased risk of RA (OR 2.5, 95% CI 1.1 to 5.4). Current and previous smoking were associated with increased risks for RA in both sexes, and in men a dose-response relationship was found with number of tobacco pack years (p for trend <0.005). The risk for RA decreased with increasing level of education in both men and women. Increased risks were seen in men born into households with private wells (OR 2.8, 95% CI 1.5 to 5.2), residentially exposed to mould (OR 4.6, 95% CI 1.1 to 20.2), or exposed to farm animals (OR 3.3, 95% CI 0.7 to 16.6). In women there were positive associations between RA and reporting a previous joint injury (OR 2.5, 95% CI 1.0 to 6.6) and prolonged exposure to hair dyes (OR 1.9, 95% CI 0.8 to 4.5). CONCLUSIONS: RA, a disease with features of T helper 1 (Th1) dominated immune response, was inversely associated with atopic allergy, a Th2 dominated condition, while there were indications of a strong positive association with Th1 related diabetes mellitus. The results support a causal relationship between smoking and RA. The level of education was inversely associated with RA, while there was a positive association between RA and certain residential factors in men and a short fertile period in women.
10616194 Crosslinking of CD44 on rheumatoid synovial cells augment interleukin 6 production. 1999 Dec CD44 is a ubiquitous molecule also known as hyaluronic acid or homing receptor. However, its cellular functions and its role in inflammation, for example rheumatoid synovitis, are currently unknown. Here we propose a novel function for CD44. Using synovial cells from patients with rheumatoid arthritis (RA), we demonstrated that CD44 crosslinking and binding to hyaluronan augmented IL-6 production. Briefly, we found that (a) rheumatoid synovial cells highly expressed CD44; (b) crosslinking of CD44 augmented IL-6 production and its mRNA transcription; (c) hyaluronan, especially when fragmented, also increased IL-6 production; and (d) CD44 activated the transcription factor activator protein-1 and CAMP-responsive element binding protein. These results indicate that the adhesion of RA synovial cells to matrices such as hyaluronic acid through CD44 could activate transcription factor, resulting in cytokine production. We therefore propose that the function of adhesion molecules as a signaling molecule may be pivotal in the pathogenesis of inflammation, including RA synovitis.
11083281 Adenovirus-mediated gene transfer of insulin-like growth factor 1 stimulates proteoglycan 2000 Nov OBJECTIVE: To examine the effect of insulin-like growth factor 1 (IGF-1) on the regulation of cartilage synthesis and other articular events in vivo. METHODS: A first-generation adenoviral vector expressing human IGF-1 (AdIGF-1) from the cytomegalovirus promoter was constructed. Particles of AdIGF-1 (5 x 10(9)) were injected through the patellar tendon into normal rabbit knee joints and rabbit knee joints with antigen-induced arthritis (AIA), with the same dose of a control adenoviral vector injected into the contralateral knees. Lavage fluids were obtained from rabbit knee joints on days 3 and 7 postinjection and used for analysis of IGF-1 expression, white blood cell infiltration, and cartilage breakdown. Cartilage chips from rabbit joints were used for assay of new proteoglycan synthesis, and tissues also were harvested from the dissected knees for histologic study. RESULTS: Intraarticular injection of AdIGF-1 resulted in a mean of 180.6 ng/ml of IGF-1 expression in the lavage fluid from rabbit joints. IGF-1 expression stimulated new proteoglycan synthesis in both naive and AIA rabbit knees, but had no significant chondroprotective or antiinflammatory effects. Histologic analysis showed that elevated levels of IGF-1 expression in both normal and arthritic knees had no adverse pathologic effects on synovium or adjacent muscles. CONCLUSION: Gene transfer of IGF-1 into rabbit knee joints promotes proteoglycan synthesis without significantly affecting inflammation or cartilage breakdown. In addition, no adverse effects following intraarticular IGF-1 gene delivery were observed. Thus, local gene transfer of IGF-1 to joints could serve as a therapeutic strategy to stimulate new matrix synthesis in both rheumatoid arthritis and osteoarthritis.
10679410 Identification of HLA-class-II-restricted epitopes of autoantigens in transgenic mice. 2000 Feb The past year has seen a spate of research in the use of HLA transgenic mice in the identification of self antigens associated with autoimmunity. Dominant T cell determinants - and, in a few cases, B cell determinants - have been characterized in the context of disease-predisposing HLA DR and DQ genes for at least three prominent and devastating autoimmune diseases: rheumatoid arthritis, multiple sclerosis and insulin-dependent diabetes mellitus.
11178127 Rheumatoid synovial CD4+ T cells exhibit a reduced capacity to differentiate into IL-4-pro 2001 CD4+ memory T cells (Tm) from rheumatoid arthritis peripheral blood (RAPB) or peripheral blood from normal donors produced IL-2, whereas fewer cells secreted IFN-gamma or IL-4 after a brief stimulation. RAPB Tm contained significantly more IFN-gamma producers than normal cells. Many rheumatoid arthritis (RA) synovial Tm produced IFN-gamma alone (40%) and fewer cells produced IL-2 or IL-4. An in vitro model was employed to generate polarized T-helper (Th) effectors. Normal and RAPB Tm differentiated into both IFN-gamma- and IL-4-producing effectors. RA synovial fluid (RASF) Tm demonstrated defective responsiveness, exhibiting diminished differentiation of IL-4 effectors, whereas RA synovial tissue (RAST) Tm exhibited defective generation of IFN-gamma and IL-4 producers.
11454065 Nitric oxide protects cultured rheumatoid synovial cells from Fas-induced apoptosis by inh 2001 Jul Nitric oxide (NO) is elevated in the synovial fluids and sera of patients with rheumatoid arthritis (RA) and is thought to be an important proinflammatory mediator in the rheumatoid synovium. To test the hypothesis that NO might modulate the apoptosis-inducing signal pathway, we investigated the effects of NO on rheumatoid synovial-cell apoptosis induced by Fas ligation with anti-Fas antibody. Pretreatment of synovial cells with the NO donor S-nitro-N-acetylpenicillamine (SNAP) prevented the Fas-mediated induction of apoptosis. The activation of caspase-3 was required to mediate Fas-induced synovial cell apoptosis. The NO donor SNAP inhibited Fas-induced caspase-3 activation in rheumatoid synovial cells. However, NO did not interrupt Fas-induced caspase-8 cleavage or subsequent cytochrome c release into the cytosol in rheumatoid synovial cells. These data indicate that NO prevents apoptosis in rheumatoid synovial cells by directly inhibiting caspase-3 activation. Thus, we propose that NO interferes with cell death signal transduction and may contribute to rheumatoid synovial cell proliferation by inhibiting induction of apoptosis.