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

The transcription and translation of interleukin-1 (IL-1) may have a pleiotropic effect on the immune system and inflammatory diseases. Recently it has been reported that human monocytes not only produce IL-1 but also induce, with adherent IgG, the secretion of an IL-1 receptor antagonist (IL-1Ra), which can play an essential in vivo and in vitro role in the regulation of IL-1 activity. Recombinant human (rh) IL-1Ra is structurally similar to IL-1 beta but with no IL-1-like activity, and specifically binds to the IL-1 receptor. To more fully evaluate and clarify the inhibitory effect of rhIL-1 receptor antagonist on IL-1 we have studied the influence of rhIL-1Ra on IL-1 transcription and translation. In this report we show that IL-1 beta mRNA from peripheral blood mononuclear cells (PBMC) is strongly inhibited (66%) when rhIL-1Ra (250 ng/ml) was added to cultured cells activated with lipopolysaccharide (LPS) (100 ng/ml) for 4 hr, determined with the slot blot analysis. The addition of exogenous rhIL-1 beta to the cell culture diminished the inhibitory effect (44%). Moreover, we report that the block of IL-1 mRNA transcription consequently leads to the inhibition of IL-1 alpha and IL-1 beta secretion in human PBMC, as measured by ELISA method. In fact, herein we show that LPS activates human PBMC to secrete IL-1 beta and IL-1 alpha, an effect inhibited, in a dose-dependent fashion by rhIL-1Ra (0.025-250 ng/ml) in an overnight incubation. Since IL-1 is a strong inducer of IL-1 synthesis in vivo and in vitro, in our study we used rh IL-1 alpha to stimulate the secretion of IL-1 beta in human PBMC. This activation, carried out overnight, also provoked the release of IL-1 beta in a dose-dependent manner, which was strongly inhibited by rhIL-1Ra used at different concentrations (0.025-250 ng/ml). The inhibitory effect exerted by IL-1Ra on human PBMC IL-1 mRNA transcription and the down-regulation of secretion of IL-1 beta stimulated by IL-1 alpha, may contribute to therapeutic effects in inflammatory diseases such as rheumatoid arthritis and other autoimmune diseases.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Inhibition of interleukin-1 beta mRNA expression and interleukin-1 alpha and beta secretion by a specific human recombinant interleukin-1 receptor antagonist in human peripheral blood mononuclear cells. 142 78

As many as 39 patients aged 16-70 years with rheumatoid arthritis (RA) lasting 3 months to 20 years were examined. The diagnostic titers of rheumatoid factor were discovered in 23 patients. The control group was made up of 26 healthy subjects (donors). The activity of IL-1 in supernatants of peripheral blood monocytes (PBM) was measured by bioassay resting on co-stimulation of mouse thymocytes; quantitative determination of tumor necrosis factor-alpha (TNF-alpha) was made by ELISA, PGE2 was determined by RIA. As compared to the controls, the RA patients manifested an increase of the production of IL-1 beta, TNF-alpha and PGE2 of PBM, which rose with the disease activity. The RA patients demonstrated direct correlations between the level of IL-1 beta, TNF-alpha and PGE2 in supernatants of PBM, whereas the donors showed up a negative correlation between IL-1 beta activity and PGE2.
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PMID:[Changes in the production of monokines and prostaglandin E2 by the peripheral blood monocytes in patients with different clinico-immunological variants of rheumatoid arthritis]. 145 68

The effects of dietary supplementation with n-3 fatty acids on the level of cytokines and complement activation in plasma from patients with rheumatoid arthritis were examined. Thirty-two patients with active rheumatoid arthritis were included in a 12-week double-blind, randomized study of dietary supplementation with n-3 fatty acids (3.6 g per day) or placebo. The cytokines were measured in plasma before and after treatment with fish oil or placebo. In general, cytokine values at the upper limits of the calculated normal areas were found. The Interleukin-1 beta concentration in plasma was reduced significantly after 12 weeks of dietary supplementation with fish oil (p < 0.03). No significant difference was observed in the placebo group. The tumour necrosis factor alpha activity in plasma did not change significantly (p = 0.167). No significant changes were observed in the degree of complement activation. The clinical status of the patients was improved in the fish oil group, but not in the placebo group, judged by Ritchie's articular index (p < 0.02). We conclude that dietary supplementation with n-3 fatty acids results in significantly reduced plasma IL-1 beta levels in patients with rheumatoid arthritis. Even though the cytokine levels were low, the anti-inflammatory effect of n-3 fatty acids could in part be explained by their ability to decrease cytokine production.
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PMID:Decreased interleukin-1 beta levels in plasma from rheumatoid arthritis patients after dietary supplementation with n-3 polyunsaturated fatty acids. 145 89

Various cytokines were recently found to be involved in the pathogenesis of rheumatoid arthritis (RA) and particularly, cytokines with hematopoietic activity have been detected in synovial tissues. We counted the number of myeloid precursors in terms of granulocyte/macrophage colony forming units (CFU-GM) and the number of stromal cell progenitors in terms of fibroblast colony forming units (CFU-F) in the tibial bone marrow adjacent to the joints affected by RA (n = 21), osteoarthritis (OA) (n = 10), and trauma (n = 2) using the colony formation unit assay. We also quantitated the amounts of interleukin 1 beta (IL-1 beta), IL-6, and granulocyte/macrophage colony stimulating factor (GM-CSF) in the culture supernatant of synovial tissue explants of these patients by enzyme linked immunosorbent assay (ELISA). The mean number (+/- SEM) of CFU-GM in patients with RA (7.4 +/- 4.9) was greater than that in patients with OA (0.5 +/- 0.2), while CFU-GM was not detected in trauma patients. The number of CFU-GM in the tibial bone marrow of patients with RA correlated well with the amount of IL-1 beta (r = 0.64, p < 0.01), but not with GM-CSF or with IL-6 from synovial tissues. These findings suggest that active bone marrow is present adjacent to the affected joints in patients with RA and that hematopoietic activity is influenced by IL-1 beta produced in nearby synovial tissues.
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PMID:Detection of myeloid precursors (granulocyte/macrophage colony forming units) in the bone marrow adjacent to rheumatoid arthritis joints. 146 60

The interleukin-6-(IL-6)-alpha dependent B-cell heterohybridomas were obtained by the fusion of X65.Ag8.653 cells with spleen cells from August rats immunized with lipopolysaccharide E. coli. One of these hybridomas (D6C8) was found to be most dependent on IL-6 for its surviving and growth. Human recombinant IL-1 beta and tumor necrosis factor-alpha could not induce the in vitro growth of this cell line. Presence of elevated level of IL-6 was demonstrated in the sera of patients with rheumatoid arthritis. A specific and sensitive detection of the IL-6 activity in test samples makes it possible to study the presence and role of IL-6 in various immunological disorders.
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PMID:[The production and characteristics of an interleukin-6-dependent hybridoma]. 146 86

This study reports on leukemia inhibitory factor (LIF) in human articular connective tissues. Biologically active LIF is present in synovial fluids from patients with osteoarthritis and at higher titers in samples from patients with rheumatoid arthritis. Cultured human synoviocytes and articular chondrocytes produced biologically active LIF and synthesized and secreted LIF proteins that migrated in SDS PAGE at approximately 43 kD. This was increased after stimulation with IL-1 beta. Chondrocytes in serum-containing cultures expressed the 4.2-kb LIF mRNA. IL-1 beta, LPS, and to a lesser extent tumor necrosis factor-alpha induced LIF gene expression. LIF autoinduced its mRNA and this provides evidence for an effect of this cytokine on function of joint tissue cells. Among a series of growth factors tested, transforming growth factor (TGF beta), including the isoforms TGF-beta1, TGF-beta 2, and TGF-beta 3, platelet-derived growth factor, basic fibroblast growth factor, and insulin-like growth factor induced this cytokine gene but differed with respect to the duration of their effects. Cultured synoviocytes expressed the LIF gene in response to the same set of peptide regulatory factors. Analysis of signal transduction pathways showed that PMA increased LIF mRNA, whereas calcium ionophore and cAMP had no detectable effects. Cycloheximide was a potent LIF mRNA inducer and dexamethasone inhibited LIF induced by PMA or IL-1 beta. Cartilage organ cultures and synovial tissues stimulated with IL-1 expressed high levels of LIF mRNA as demonstrated by in situ hybridization. These results identify LIF as a new cytokine that is produced by joint tissue cells and is overexpressed in arthritis. The induction of this cytokine by factors that are present during joint inflammation and the effects of LIF on connective tissue cells suggest that LIF is a mediator that can contribute to the pathogenesis of arthritis.
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PMID:Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis. 152 40

Interleukin 1 receptor antagonist (IL-1ra) has been found in glycosylated form in the urine of febrile patients or of children with rheumatoid arthritis, and in the supernatant of monocytes cultured in the presence of immune complexes. It blocks competitively the binding of IL-1 alpha and beta to their receptors. Produced amongst others by mononuclear cell lines and matured monocytes and alveolar macrophages, it prevents prostaglandin E2 and collagenase production by fibroblasts and synovial cells. In mice, IL-1ra improves survival after lethal endotoxemia. In this study, both natural and recombinant human IL-1ra (rhIL-1ra) were tested in an allogeneic T-cell reaction, and in mitogen- or antigen-induced lymphocyte proliferation. Neither the natural nor the rhIL-1ra blocked T-cell proliferation, but rhIL-1ra abolished the effect of exogenous IL-1 beta. This was not due to a loss of bioactivity of IL-1ra in culture, as the IL-1ra of the supernatant still completely inhibited 125I-IL-1 alpha binding to EL 4-6.1 cells and markedly reduced PGE2 production during antigen presentation. We conclude that IL-1ra alone, even at high concentrations, is not sufficient to block human T-cell proliferation in vitro.
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PMID:Natural and recombinant interleukin 1 receptor antagonist does not inhibit human T-cell proliferation induced by mitogens, soluble antigens or allogeneic determinants. 153 18

Rheumatoid arthritis (RA) is associated with T- and B-cell dysfunction. Immunoglobulin (Ig) production is under the control of T cells and their derived cytokines such as interleukin 2 (IL-2) and IL-4. Herein we studied the regulation of the production of immunoglobulins and cytokines by peripheral blood mononuclear cells from RA patients and controls. In the controls, IL-4 inhibited Ig production in response to Staphylococcus aureus and pokeweed mitogen stimulation. IL-2 induced maximal Ig production in association with Staphylococcus aureus, whereas it inhibited pokeweed mitogen-induced production. In patients, levels of Ig production in response to mitogens and cytokines were reduced, particularly for the response to IL 2. The inhibitory effect of IL-4 on mitogen-induced Ig production was observed in RA patients as in the controls. Spontaneous production of IL-6 was increased in RA patients. These levels were correlated with indicators of active disease such as sedimentation rate and Ritchie index. IL-4 inhibited the production of IL-6, IL-1 beta, and tumor necrosis factor alpha (TNF alpha) by both controls and rheumatoid patients. Thus as first described for the T-cell response, mononuclear cells from RA patients display a reduced response to mitogens and cytokines which induce their B-cell differentiation into Ig-screening cells. However, IL-4 was able to inhibit Ig and cytokine production, properties suggesting a potential antiinflammatory role for this cytokine.
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PMID:Interleukin 4 inhibits polyclonal immunoglobulin secretion and cytokine production by peripheral blood mononuclear cells from rheumatoid arthritis patients. 155 40

Although interferon-gamma has been shown to effectively prime macrophages for enhanced production of tumor necrosis factor-alpha (TNF alpha), it is reasonable to assume that other cytokines present in the extracellular environment may likewise facilitate cytokine biosynthesis. For example, interleukin-6 (IL-6) is synthesized by synovial lining macrophages and fibroblasts, and has been detected (along with TNF alpha) in rheumatoid synovial effusions. Therefore, the purpose of the present study was to determine whether IL-6 influences the production of IL-1 beta and/or TNF alpha by THP-1 macrophages. Although IL-6 treatment alone resulted in only a slight increase in TNF alpha levels, administration of IL-6 followed by Sal. minnesota LPS resulted in a synergistic potentiation of TNF alpha production by THP-1 macrophages. The priming effect of IL-6 could be reversed by boiling, or by the addition of a neutralizing polyclonal antibody against IL-6. Notably, IL-6 only weakly enhanced interleukin-1 beta production. In summary, the ability of IL-6 to potentiate TNF alpha production by THP-1 macrophages may provide insight into the regulation of the cytokine network in inflammatory diseases, such as rheumatoid arthritis.
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PMID:Interleukin-6 can prime THP-1 macrophages for enhanced production of tumor necrosis factor-alpha in response to LPS. 160 43

In situ hybridization was used to localize stromelysin mRNA in rheumatoid arthritis synovial tissue. Stromelysin antisense probes hybridized primarily to the intimal lining layer in frozen tissue sections, with little or no sublining signal. The expression of stromelysin correlated with cellularity as determined by hybridization with an actin probe. Double-label experiments were performed to detect tissue inhibitor of metalloproteinases (TIMP) and stromelysin mRNA simultaneously in synovial tissue. Coexpression of both mRNA species was identified in a subpopulation of intimal lining cells. In some highly inflammatory tissues, virtually all of the lining cells hybridized to both probes. However, in other tissues, expression of the two genes was discordant, with large numbers of TIMPpositive/stromelysin(negative) cells. Similar results were observed with late-passage cultured synoviocytes. Unstimulated cells did not express the stromelysin gene, whereas TIMP was constitutively produced. Addition of interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha) to cultures induced the former but had little effect on the latter. Double-label experiments clearly showed discordant expression in individual cells. Stromelysin and TIMP genes likely have distinct transcriptional controls that provide precise control over the local environment and matrix turnover.
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PMID:Stromelysin and tissue inhibitor of metalloproteinases gene expression in rheumatoid arthritis synovium. 160 5


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