Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the therapeutic potential and mechanism of action of IFN-beta protein for the treatment of rheumatoid arthritis (RA). Collagen-induced arthritis was induced in DBA/1 mice. At the first clinical sign of disease, mice were given daily injections of recombinant mouse IFN-beta or saline for 7 days. Disease progression was monitored by visual clinical scoring and measurement of paw swelling. Inflammation and joint destruction were assessed histologically 8 days after the onset of arthritis. Proteoglycan depletion was determined by safranin O staining. Expression of cytokines, receptor activator of NF-kappaB ligand, and c-Fos was evaluated immunohistochemically. The IL-1-induced expression of IL-6, IL-8, and granulocyte/macrophage-colony-stimulating factor (GM-CSF) was studied by ELISA in supernatant of RA and osteoarthritis fibroblast-like synoviocytes incubated with IFN-beta. We also examined the effect of IFN-beta on NF-kappaB activity. IFN-beta, at 0.25 microg/injection and higher, significantly reduced disease severity in two experiments, each using 8-10 mice per treatment group. IFN-beta-treated animals displayed significantly less cartilage and bone destruction than controls, paralleled by a decreased number of positive cells of two gene products required for osteoclastogenesis, receptor activator of NF-kappaB ligand and c-Fos. Tumor necrosis factor alpha and IL-6 expression were significantly reduced, while IL-10 production was increased after IFN-beta treatment. IFN-beta reduced expression of IL-6, IL-8, and GM-CSF in RA and osteoarthritis fibroblast-like synoviocytes, correlating with reduced NF-kappaB activity. The data support the view that IFN-beta is a potential therapy for RA that might help to diminish both joint inflammation and destruction by cytokine modulation.
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PMID:Treatment with recombinant interferon-beta reduces inflammation and slows cartilage destruction in the collagen-induced arthritis model of rheumatoid arthritis. 1514 70

Interleukin-23, a recently described cytokine produced by activated antigen-presenting cells, including dendritic cells, is a p19/p40 heterodimer. The p40 subunit is shared with IL-12, the major Th1-driving cytokine, while p19 is distantly related to IL-12 p35. IL-23 has pro-inflammatory actions, inducing IL-17 secretion from activated CD4+ T cells, and stimulating the proliferation of memory CD4+ T cells. Here, we examined the effects of PGE2, a well-known immunomodulator, on the production of IL-23 by bone marrow- derived dendritic cells (BM-DCs). Our results indicate that PGE2 increases the production of functional IL-23 from immature BM-DCs in a time- and dose-dependent manner. PGE2 induces both the expression of p19 and p40, without affecting p35 expression. The effect of PGE2 is mediated through the specific receptors EP2/4 and is mimicked by cAMP-inducing agents, such as forskolin and dbcAMP. Although PGE2 also induces IL-1beta and IL-6 expression in non-stimulated DCs, the stimulatory effect of PGE2 on IL-23 production is not mediated through IL-1beta or IL-6. GM-CSF, the pro-inflammatory cytokine required for the generation of BM-DCs, amplifies the IL-23 inducing activity of PGE2 in a synergistic manner. Recent studies described both pro- and anti-inflammatory effects of PGE2, and our results suggest an additional mechanism for its pro-inflammatory role, particularly significant for autoimmune diseases, such as rheumatoid arthritis.
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PMID:Prostaglandin E2 induces IL-23 production in bone marrow-derived dendritic cells. 1518 Sep 65

We have recently shown that granulocyte-colony-stimulating factor (G-CSF)- and interferon-gamma (IFN-gamma)-activated human neutrophils accumulate and release remarkable amounts of soluble B-lymphocyte stimulator (BLyS) in vitro. In this study, we provide evidence that neutrophils migrating into skin window exudates (SWEs) developed in healthy volunteers and in patients with rheumatoid arthritis (RA), synthesized, and released BLyS in response to locally produced G-CSF. Accordingly, the concentrations of soluble BLyS in SWEs were significantly more elevated than in serum. Because the levels of SWE BLyS, but not SWE G-CSF, were higher in patients with RA than in healthy subjects, we examined the effect of CXCL8/IL-8, C5a, and other proinflammatory mediators that dramatically accumulate in RA SWEs and in inflamed synovial fluids. We show that CXCL1/GROalpha, CXCL8/IL-8, C5a, immune complexes, tumor necrosis factor-alpha (TNF-alpha), leukotriene B4, N-formyl-methionyl-leucyl-phenylalanine (fMLP), and lipopolysaccharide (LPS), which by themselves do not induce BLyS de novo synthesis, act as potent secretagogues for BLyS, which is mainly stored in Golgi-related compartments within G-CSF-treated neutrophils, as determined by immunogold electron microscopy. This action is pivotal in greatly amplifying neutrophil-dependent BLyS release in SWEs of patients with RA compared with healthy subjects. Collectively, our data uncover a novel mechanism that might dramatically exacerbate the release of BLyS by neutrophils during pathologic inflammatory responses.
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PMID:Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases. 1535 25

Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat the condition of rheumatoid arthritis, where levels of prostaglandin E2 (PGE2) and granulocyte macrophage-colony stimulating factor (GM-CSF) are elevated in the synovial fluid. NO-NSAIDs are a new class of cyclooxygenase (COX)-inhibitors developed by coupling a nitric oxide (NO)-donating moiety to conventional NSAIDs. We show that, in cytokine-treated synoviocytes (from non-rheumatic patients), NO-naproxen and NO-flurbiprofen like their parent compounds concentration-dependently reduce the levels of PGE2 (an index of COX-2 activity), with a corresponding rise in the release of GM-CSF. Unlike acetylsalicylic acid (ASA), NO-ASA reduces the levels of PGE2, without increasing GM-CSF release, although cell viability is reduced at the highest concentration (1 mM). The effects of NSAIDs and NO-NSAIDs on GM-CSF release were attributable to the PGE2 mediated cyclic (c) AMP pathway because PGE2 reversed the effects of COX blockade. Second, phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX) and Ro-201724 (both of which elevate cAMP levels) decreased GM-CSF release, in the presence of PGE2. Finally, neither sodium nitroprusside nor zaprinast (both of which elevate cGMP levels) affected GM-CSF or PGE2 release. Our findings demonstrate that GM-CSF is regulated by NSAIDs and NO-NSAIDs via inhibition of COX and appears to be mediated via the cAMP pathway. NO-ASA is the exception, because it does not increase GM-CSF release, although at millimolar concentrations cell viability is reduced.
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PMID:NSAIDs increase GM-CSF release by human synoviocytes: comparison with nitric oxide-donating derivatives. 1568 Feb 49

Clinical trials evaluating tumor necrosis factor alpha (TNF-alpha) binding agents in patients with rheumatoid arthritis (RA) have demonstrated significant efficacy in reducing symptoms of disease and slowing radiographic progression. However, infectious complications are the most severe and common adverse effects of anti-TNF therapy. The functional capacities of neutrophils (PMNs) as the first line of defense in bacterial and fungal infections are enhanced by soluble TNF as a potent neutrophil primer. The aim of this study was to assess the influence of in vivo TNF blockade on oxygen burst (OB) and phagocytosis of human neutrophils. PMNs were derived from 20 patients with RA on anti-TNF-alpha therapy and 13 patients using conventional DMARDs. By flow cytometry we measured OB upon stimulation with Escherichia coli and N-formyl-1-methionyl-1-leucyl-phenylalanine (FMLP) with and without priming with granulocyte-colony stimulating factor (G-CSF) and/or TNF-alpha using dihydrorhodamine (DHR) 123. Phagocytosis of fluorescein isothiocyanate (FITC)-labeled E. coli was also assessed by flow cytometry. Thirty-three healthy volunteers served as controls. Upon stimulation with E. coli and FMLP, there was no significant difference in OB between the two patient groups and healthy controls. Priming was effective in all groups. Phagocytosis of E. coli by PMNs was equally effective in controls and patients independent from the treatment regimen. These data show that OB, phagocytosis and responsiveness to priming with TNF and G-CSF of PMNs are not impaired in patients with RA treated with anti-TNF agents in comparison with patients on conventional DMARDs or healthy controls. Thus, the infectious complications observed in patients with TNF blockade cannot be explained by functional impairment of PMNs; however, the neutralization of TNF as a potent primer of neutrophil response may increase the susceptibility for infections in these patients.
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PMID:Blockade of TNF does not alter oxygen burst and phagocytosis of human neutrophils in patients with rheumatoid arthritis. 1580 45

Synovial fluid from patients with various arthritides contains procoagulant, cell-derived microparticles. Here we studied whether synovial microparticles modulate the release of chemokines and cytokines by fibroblast-like synoviocytes (FLS). Microparticles, isolated from the synovial fluid of rheumatoid arthritis (RA) and arthritis control (AC) patients (n = 8 and n = 3, respectively), were identified and quantified by flow cytometry. Simultaneously, arthroscopically guided synovial biopsies were taken from the same knee joint as the synovial fluid. FLS were isolated, cultured, and incubated for 24 hours in the absence or presence of autologous microparticles. Subsequently, cell-free culture supernatants were collected and concentrations of monocyte chemoattractant protein-1 (MCP-1), IL-6, IL-8, granulocyte/macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF) and intracellular adhesion molecule-1 (ICAM-1) were determined. Results were consistent with previous observations: synovial fluid from all RA as well as AC patients contained microparticles of monocytic and granulocytic origin. Incubation with autologous microparticles increased the levels of MCP-1, IL-8 and RANTES in 6 of 11 cultures of FLS, and IL-6, ICAM-1 and VEGF in 10 cultures. Total numbers of microparticles were correlated with the IL-8 (r = 0.91, P < 0.0001) and MCP-1 concentrations (r = 0.81, P < 0.0001), as did the numbers of granulocyte-derived microparticles (r = 0.89, P < 0.0001 and r = 0.93, P < 0.0001, respectively). In contrast, GM-CSF levels were decreased. These results demonstrate that microparticles might modulate the release of chemokines and cytokines by FLS and might therefore have a function in synovial inflammation and angiogenesis.
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PMID:Synovial microparticles from arthritic patients modulate chemokine and cytokine release by synoviocytes. 1589 40

Cytokines (interleukins, chemokines, and some growth factors) play an important role in cancer, metabolic disorders, autoimmune disorders and inflammatory diseases, such as rheumatoid arthritis, asthma, Crohn's disease, psoriasis, multiple sclerosis and asthma. Cytokine-based drugs and anticytokine therapies are an increasingly important class of drugs in the treatment and management of many diseases. Interferons are being used to treat viral diseases and cancers. Anti-tissue necrosis factor therapies, such as Enbrel (etanercept; Immunex Corp) and Remicade (infliximab; Centocor) have demonstrated clinical efficacy in rheumatoid arthritis and Crohn's disease. In addition, thalidomide (Celgene) is being used to treat erythema nodosum in leprosy, cancers (multiple myeloma and colon cancer) and autoimmune diseases. This conference focused on new developments in basic research, drug discovery and clinical development of cytokine-based drugs.
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PMID:Cytokines as drug targets. 1601 67

The current study explored our hypothesis that IFN-gamma-producing human T cells inhibit human osteoclast formation. Activated T cells derived from human PBMC were divided into IFN-gamma-producing T cells (IFN-gamma(+) T cells) and IFN-gamma-non-producing T cells (IFN-gamma(-) T cells). IFN-gamma(+) T cells were cultured with human monocytes in the presence of macrophage-CSF alone. The concentration of soluble receptor activator of NF-kappaB ligand (RANKL) and IFN-gamma, and the amount of membrane type RANKL expressed on T cells, were measured by ELISA. In the patients with early rheumatoid arthritis (RA) treated with non-steroidal anti-inflammatory drugs alone, CD4+ T cells expressing both IFN-gamma and RANKL were detected by flow cytometry. Surprisingly, IFN-gamma(+) T cells, but not IFN-gamma(-) T cells, induced osteoclastogenesis from monocytes, which was completely inhibited by adding osteoprotegerin and increased by adding anti-IFN-gamma antibodies. The levels of both soluble and membrane type RANKL were elevated in IFN-gamma(+) T cells. The ratio of CD4+ T cells expressing both IFN-gamma and RANKL in total CD4+ T cells from PBMC was elevated in RA patients. Contrary to our hypothesis, IFN-gamma(+) human T cells induced osteoclastogenesis through the expression of RANKL, suggesting that Th1 cells play a direct role in bone resorption in Th1 dominant diseases such as RA.
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PMID:IFN-gamma-producing human T cells directly induce osteoclastogenesis from human monocytes via the expression of RANKL. 1622 May 42

To determine whether synovial fluid (SF) macrophages isolated from the SF of osteoarthritis (OA), rheumatoid arthritis (RA) and pyrophosphate arthropathy (PPA) joints are capable of osteoclast formation, and to investigate the cellular and humoral factors required for this to occur, SF macrophages (CD14+) were isolated from the knee joint SF from patients with OA, RA and PPA and cultured for up to 14 days with macrophage-colony stimulating factor (M-CSF) and soluble receptor activator for nuclear factor-kappaB ligand (RANKL) or tumour-necrosis factor-alpha (TNFalpha) and interleukin-1alpha (IL-1alpha). Osteoclast differentiation was assessed by expression of tartrate-resistant acid phosphatase (TRAP) and vitronectin receptor (VNR), F-actin ring formation and lacunar resorption. Osteoclast formation and lacunar resorption was seen in RANKL-treated cultures of SF macrophages isolated from OA, RA and PPA joints with the largest amount of resorption noted in RA and PPA SF macrophage cultures. In TNFalpha/IL-1alpha-treated RA and PPA SF macrophage cultures, osteoclasts capable of lacunar resorption were also formed. Lacunar resorption was more extensive in RANKL than TNFalpha/IL-1alpha-treated cultures. These findings indicate that SF macrophages are capable of differentiating into mature osteoclasts capable of lacunar resorption. M-CSF in combination with RANKL or TNFalpha/IL-1alpha was required for osteoclast formation. As inflammatory synovial fluids contain an increase in the number of macrophages and an increase in the amounts of RANKL, TNFalpha and IL-1alpha, these findings suggest that one means whereby bone erosions may form in rheumatoid or crystal arthritis is by differentiation of synovial fluid macrophages into osteoclasts.
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PMID:Synovial fluid macrophages are capable of osteoclast formation and resorption. 1627 18

The human polyomavirus JC virus (JCV) is ubiquitous and can be shed in the urine of more than 40% of the healthy population. Amplification and sequencing of JCV from urine has allowed a distinctive map of the distribution of JCV genotypes worldwide. To define the frequency of JCV urinary excretion and genotype distribution in Ireland, urines from 121 healthy individuals and from 94 immunocompromised individuals (human immunodeficiency virus [HIV]-positive patients and rheumatoid arthritis patients) were collected. JCV DNA was detected by polymerase-chain reaction (PCR) with subsequent nucleotide sequencing of a fragment of the major capsid protein (VP1). JCV was detected in 20.7% of healthy individuals and was found significantly more often in the urine of HIV-positive patients (54.2%; P < .001) and rheumatoid arthritis patients (54.4%; P < .001). In healthy Irish individuals genotype 1 was the predominant genotype in 62.5%, followed by genotype 4 in 16.7% and genotype 2 in 12.5%. In contrast, genotype 2 was significantly more often isolated from the urine of both HIV-positive patients (60%) and rheumatoid arthritis patients (54.4%; P < .01). The pattern of genotype distribution among healthy Irish individuals is in agreement with data reported from other European countries, whereas the overall level of JCV urinary excretion is lower. Previous studies have found genotype 2 significantly more often in cerebrospinal (CSF) samples of patients with progressive multifocal leukoencephalopathy (PML). Here the authors report an increased frequency of genotype 2 in urine samples of immunocompromised non-PML patients. This finding further underlines the hypothesis that there could be biologic differences between JCV genotypes.
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PMID:JC virus in the Irish population: significant increase of genotype 2 in immunocompromised individuals. 1659 73


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