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 synovium in rheumatoid arthritis (RA) is characterized by an increase in lining layer thickness and infiltration of inflammatory cells into the sublining area. Fibroblasts in the lining layer develop the appearance of "transformed cells", under the influence of proto-oncogenes involved in the regulation of the cell cycle. Fibroblast and macrophage-derived cytokines such as IL-1 and TNF-alpha are present abundantly in the rheumatoid synovium and stimulate these cells to produce destructive enzymes. Other cytokines such as IL-4 and IL-10 represent a physiological attempt to reverse the inflammatory process. Adhesion molecules facilitate both the migration of cells to the joint as well as the attachment of synovium to bone and cartilage. Joint destruction is mediated by enzymes such as serine proteases, matrix metalloproteinases (MMPs) and the cathepsins. Treatments directed against various components of the inflammatory cascade have shown promise. Inhibition of MMPs or adhesion molecules, blockade of IL-1 or TNF-alpha and the use of anti-Fas antibodies to induce apoptosis offer new possibilities for the treatment of RA. More recently, the employment of genes with antiarthritic properties has shown therapeutic potential.
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PMID:Mechanism of joint destruction in rheumatoid arthritis. 951 Sep 39

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the accumulation of inflammatory cells into the synovium and the destruction of joints. Cytokines are important regulators of the synovial inflammation. Some cytokines, such as tumour necrosis factor (TNF)-alpha and interleukin (IL)-1, function by promoting inflammatory responses and by inducing cartilage degradation. Other cytokines, such as IL-4, IL-10 and IL-13, function mainly as anti-inflammatory molecules. Although anti-inflammatory cytokines are present in rheumatoid joints, in progressive RA their levels obviously are too low to neutralize the deleterious effects of proinflammatory cytokines. Inhibiting the action of proinflammatory cytokines by using specific cytokine inhibitors or anti-inflammatory cytokines is the basis for new therapies currently tested in patients with RA. Promising results on the use of neutralizing anti-TNF-alpha monoclonal antibodies in the treatment of RA have been reported. The results from a trial using recombinant IL-10 in the treatment of patients with RA are available in the near future and will be important in determining the therapeutic potential of this cytokine.
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PMID:Pro- and anti-inflammatory cytokines in rheumatoid arthritis. 956 16

Rheumatoid arthritis is an autoimmune disease that causes inflammation mainly in synovial tissues. RA manifests as a chronic polyarthritis with intermittent acute inflammatory episodes. The inflammatory sites are characterized by infiltration of activated lymphocytes and macrophages into the synovial membrane, and the proliferation of synovial cells. The local production of a number of cytokines by proliferative synovial cells as well as by infiltrating cells appears to account for many of the pathological and clinical manifestations in rheumatoid arthritis. Tissues were collected from twelve RA patients undergoing joint replacement surgery. The synovium was collected and the cell types were identified, and markers for chronic and acute inflammatory mediators were measured. The cells types found in the synovium are capable of secreting cytokines which are capable of both acute inflammation (IL-1, IL-6, IL-8, MCP-1 and TNF), as well as chronic inflammation (IL-2, IL-10, and IL-4). The results obtained showed that the macrophages-derived acute inflammatory cytokines (IL-1, IL-6 and IL-8) were easily detected at levels of 22.6 +/- 12 pg/mg protein; 48.5 +/- 42 pg/mg protein, and 76 +/- 31 pg/mg protein; respectively. T-cell derived chronic inflammation cytokines (IL-2, IL-4 and IL-10) were rarely detected. Retrieved tissues that immunostained positive for IL-6, IL-1 and IL-8 also is suggestive of an acute inflammatory response. The results clearly demonstrate that the acute response may be responsible for the subsequent need for joint arthroplasties.
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PMID:Synovial tissues collected from rheumatoid patients undergoing total joint arthroplasty express markers for acute inflammation. 960 33

Hormonal factors linked to age, gender, and reproductive status are undoubtedly involved in regulating the onset of numerous autoimmune diseases. For example, systemic lupus erythematosus (SLE), a disease characterized by immune complex-mediated pathology linked to excess Th2 cytokine production (e.g., IL-10) primarily affects women in the reproductive years. Rheumatoid arthritis (RA), a disease characterized primarily by cell-mediated joint immunopathology linked to deficient Th2 cytokine production, is also more common in women, but, in contrast to SLE, the highest incidence is at menopause. Pregnancy-associated changes in these diseases, however, provide the most compelling evidence that hormonal factors play a major role in modulating the expression of these diseases. SLE often flares during pregnancy, whereas RA commonly remits during pregnancy and flares or initially develops in the postpartum period. These observations appear to be explained by the accumulating data indicating that during pregnancy cell-mediated immune function and Th1 cytokine production (e.g., IL-12, interferon-gamma) are suppressed, and humoral immunity and Th2 cytokine production (e.g., IL-4, IL-10) are enhanced. These patterns reverse in the postpartum period. In other words, antithetical Th1/Th2 cytokine profiles appear to characterize pregnancy and the postpartum period. Strong evidence now indicates that changes in the production of cortisol, progesterone, and estrogen play a major role in modulating Th1/Th2 cytokine balance.
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PMID:Hormones, pregnancy, and autoimmune diseases. 962 35

IL-17 is a cytokine produced by CD4 T cells that activates the production of inflammatory mediators by synoviocytes. To study the contribution of soluble factors in the interaction between T cells and synoviocytes in rheumatoid arthritis (RA), we looked at the effect of IL-17 on these cells in the presence of cytokines classified as pro (IL-1)- and anti-inflammatory (IL-4, IL-13, IL-10). Both human rIL-1beta and rIL-17 induced IL-6 and leukemia inhibitory factor (LIF) production by synovial fibroblasts in a dose-dependent manner. After 7 days of culture, optimal concentrations of IL-1beta increased IL-6 (33-fold) and LIF (10-fold) production by synoviocytes, while IL-17 showed a lesser effect on IL-6 (17-fold) and LIF (4-fold) production. Using low concentrations of IL-17 and IL-1beta in combination, a synergistic effect was observed on the production of IL-6, whereas an additive effect was observed for LIF production. Production of biologically active IL-17 was demonstrated in RA synovium supernatants with the use of a blocking anti-IL-17 Ab. Both IL-4 and IL-13 had a modest stimulatory effect on IL-1- and IL-17-induced production of IL-6, but inhibited that of LIF. In contrast, IL-10 had a limited inhibitory effect on IL-6 production and no effect on that of LIF. These findings indicate that low levels of cytokines produced by monocytes (IL-1) and T cells (IL-17) can act together on synoviocytes. Thus, some RA synovium T cells producing IL-17 can activate mesenchymal cells leading to an increased proinflammatory pattern sensitive to Th2 cytokine regulation.
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PMID:Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. 964 50

The synovial membrane in osteoarthritis (OA) often exhibits inflammatory infiltrates, but the role of T cells in these infiltrates is not known. T-cell activation antigens were analyzed by immunohistochemistry, and T-cell cytokine transcripts were measured by competitive PCR in synovial membranes from patients with OA and rheumatoid arthritis (RA). Lymphoid cell aggregates, containing primarily CD3+ T lymphocytes, were found in 65% of patients with OA. Mononuclear cells expressing the activation antigens CD69, CD25, CD38, CD43, CD45RO, and HLA class II were present in both patient groups, although in higher numbers in patients with RA. Interleukin 2 (IL-2) transcripts were found in 10 of 18 patients with OA versus 12 of 13 patients with RA (P = 0.03). Gamma interferon (IFN-gamma) transcripts were detected in 9 of 18 patients with OA versus 10 of 13 patients with RA (not significant), whereas IL-10 transcripts were found in nearly all patients. IL-4 and IL-5 were not detected in any patients. The levels of IFN-gamma and IL-2 transcripts, normalized for T-cell number equivalents, were not statistically different between OA and RA, but the levels of IFN-gamma, normalized for total cell number equivalents, were lower in OA than in RA (P = 0.01). Synovial membranes that expressed IL-2 and IFN-gamma transcripts were more likely to have heavier infiltrations of T cells and cells bearing activation markers than synovial membranes that did not express these cytokines. The presence of activated T cells and TH1 cytokine transcripts in chronic joint lesions of patients with OA suggests that T cells contribute to chronic inflammation in a large proportion of these patients.
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PMID:T cells and T-cell cytokine transcripts in the synovial membrane in patients with osteoarthritis. 966 43

Adhesion molecules and cytokines are important in chronic inflammatory conditions such as rheumatoid arthritis (RA) by virtue of their role in cell activation and emigration. Using immunohistochemical techniques we studied the expression of adhesion molecules and cytokines in cryopreserved sections of murine knee joint in the course of antigen-induced arthritis, an animal model of human RA. Various adhesion molecules and cytokines are expressed in the arthritic joint tissue. LFA-1, Mac-1, CD44, ICAM-1 and P-selectin were strongly expressed in the acute phase and to a lesser degree in the chronic phase of arthritis. VLA-4 and VCAM-1 appeared to be moderately expressed on day 1, L-selectin between days 1 and 3. LFA-1, Mac-1, CD44, alpha 4-integrin, ICAM-1 and the selectins were found expressed on cells of the synovial infiltrate, LFA-1, Mac-1 and ICAM-1 on the synovial lining layer, and VCAM-1 and P-selectin on endothelial cells. Expression of E-selectin could be demonstrated throughout the experiment at a low level in cells of the acute cell infiltrate. Cytokines, especially IL-2, IL-4, IL-6, TNF, and IFN-gamma, were heavily expressed during the acute phase of arthritis in cellular infiltrate. Taken together these data demonstrate that cytokines and their activation of adhesion molecules contribute to cell infiltration and activation during the initial phase of arthritis and to the induction and progression of tissue destruction in arthritic joints. These molecules might be potential targets for novel therapeutic strategies in inflammatory and arthritic disorders.
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PMID:Expression of cell adhesion molecules and cytokines in murine antigen-induced arthritis. 975 22

THE CONCEPT OF GENE THERAPY: Gene therapy is applicable in diseases involving several genes such as rheumatoid arthritis. Gene transfer is the insertion in vivo of genetic material necessary to produce a molecule with therapeutic action. This strategy is currently in experimental stages; feasibility studies in humans are in the preliminary stage. SEVERAL TARGETS: In experimental models of rheumatoid arthritis, the most widely studied target genes are those which code for inflammation inhibitors such as IL-1 receptor antagonists or anti-inflammatory cytokines (IL-4, IL-10, IL-13). Another interesting target would concern genes coding for molecules inhibiting joint destruction (for example metalloprotease inhibitors). VECTORS: The development of high-performance vectors (both viral and nonviral vectors) will greatly improve the expected benefit/risk potential of gene therapy in general. IN RHEUMATOID ARTHRITIS: The particular problem in rheumatoid arthritis is the choice of the transfection site. An articular site would require multiple injections in the different affected joints. A systemic approach would take into account the general disseminated nature of the disease.
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PMID:[Gene therapy in rheumatoid polyarthritis: perspectives]. 976 55

Ets-1 is a transcription factor with restricted expression in lymphocytes, and it has been implicated in the regulation of T cell genes such as TCR alpha, TCR beta, CD4, IL-2, and TNF-alpha. We show in this study that Ets-1 is also expressed in some mast cells constitutively and can be induced in primary mast cells with stimuli that activate mast cells. We also show that Ets-1 plays a role in the regulation of granulocyte-macrophage CSF (GM-CSF), a cytokine expressed by activated mast cells. We have characterized a murine growth factor-independent mast cell line, FMP6-, derived from a factor-dependent cell line, FMP1.6. FMP6- has acquired a distinct connective tissue mast cell-like phenotype, as characterized by the expression of mast cell proteases MMCP-4 and MMCP-6, expression of IL-12, and the down-regulation of IL-4. The parental FMP1.6 cell line displays a mucosal mast cell-like phenotype. FMP6- cells have increased Ets-1 expression and achieve growth-factor independence by the autocrine production of GM-CSF and IL-3. Transient transfection of an Ets-1 expression construct in FMP6- cells results in transactivation of a GM-CSF reporter, while a point mutation in the consensus Ets binding site in the conserved lymphokine element, CLE0, abolishes Ets-1 transactivation. Importantly, antisense Ets-1 demonstrates an ability to repress the activity of the GM-CSF reporter. These data suggest a role for Ets-1 in mast cell growth regulation and activation, and because of the central role of mast cells in inflammatory processes, such as asthma and rheumatoid arthritis, they identify Ets-1 as potentially contributing to the pathophysiology of such diseases.
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PMID:The role of Ets-1 in mast cell granulocyte-macrophage colony-stimulating factor expression and activation. 978 Jan 81

T cells produce regulatory cytokines which control inflammation. In rheumatoid arthritis (RA), a Th1 cytokine profile has been described in the synovium. In order to assess the Th1/Th2 cytokine balance in blood, a one step culture-immunoassay procedure was used to measure the ex vivo production of IFN gamma and IL-4 by whole blood cells from 26 RA patients and 25 controls. For comparison, the same cytokines were measured by ELISA in supernatants of activated whole blood cells. The direct whole blood assay was 10-fold more sensitive than standard ELISA to measure IL-4 levels. IL-4 production was higher in RA patients than in controls, whereas that of IFN gamma was lower. Accordingly, the IL-4/IFN gamma ratio, which reflects the Th2/Th1 cytokine balance in blood, was higher in RA patients (P < 0.0001). The present findings indicate a Th2-over-Th1 cytokine balance profile in RA blood. These results are in contrast with the Th1-over-Th2 pattern previously found in the joint, indicating that the two compartments appear to be differently regulated.
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PMID:Increased production of a Th2 cytokine profile by activated whole blood cells from rheumatoid arthritis patients. 985 84


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