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)

Rheumatoid arthritis (RA) is an immune disease in which the pathological immune reaction is thought to be initiated by the presentation of an (auto) antigen or superantigen by MHC class II positive cells to CD4 T cells. These successive immunological events can be studied by the cytokines produced at the different stages. Cytokine secretion by stimulated cells in autologous diluted whole blood has allowed the study of the immune profile characteristic of rheumatoid arthritis. The pattern of RA patient whole blood cells cultured in autologous blood is characterized by hyperactivity of the mononuclear cells with high secretion of IL-1 beta, TNF-alpha and IL-6 and low production of IFN-gamma, in comparison with the normal (N) and osteoarthrosis (OA) populations. The IL-2 secretion pattern is unique, arising from production followed by consumption. This production-consumption turnover is the most elevated in the RA group. The T cells are indeed activated in rheumatoid arthritis but regulatory events suppress some of their functions. A correlation was found between the inflammatory proteins and mediators of cellular immunity and macrophagic function: IL-1 beta and the sedimentation rate; IL-6 and fibrinogen; TNF-alpha and the number of blood monocytes. The secretion of OA-stimulated whole blood cells was similar to RA for two monokines (overproduction of TNF-alpha and IL-6) and different for IL-1 beta, not different from normal in OA. Stimulated whole blood cell cytokine secretion profile from RA and OA groups, was the same as previously observed in synovial fluid.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma and GM-CSF) in whole blood: II. Application to rheumatoid arthritis and osteoarthritis. 129 40

In order to investigate the relationships between cytokine production and arthritic disease we have determined the concentrations of immunoreactive interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, tumour necrosis factor-alpha (TNF-alpha), interferon-alpha (IFN-alpha), IFN-gamma, and soluble IL-2-receptor (sIL-2R), as well as bioactive IL-1 and IL-6, in synovial fluids (SF) and plasma of patients with a variety of arthritides. Careful assay revealed only minimal concentrations of IL-1, particularly its biologically active form, in SF. No IL-1 was detectable in the plasma of patients that had IL-1 in their SF. Concentrations of both immunoreactive IL-1 beta and TNF-alpha in SF of rheumatoid arthritis (RA) patients were significantly higher than those in SF from patients with other inflammatory arthritides or osteoarthritis (OA). IL-6 and sIL-2R concentrations in both SF and plasma were higher in RA patients than in OA patients, and were significantly correlated. Approximately half of the SF from patients with all arthropathies contained detectable IFN-alpha, whilst IFN-Y was present in less than 10%. There were significant associations between IL-6, sIL-2R, IL-1 beta, TNF-alpha and IFN-alpha. The concentration of these cytokines, where detectable, was also related to leukocyte counts in the SF, as well as to parameters assessing local and systemic disease activity. Although IL-6 was the cytokine most clearly related to other cytokines, and to parameters assessing disease activity, the relationship between general articular disease activity and IL-6 was only evident in patients with arthropathies other than rheumatoid arthritis.
 ...
PMID:Cytokine inter-relationships and their association with disease activity in arthritis. 846 37

The presence of activated T cells in the synovial membrane of patients with rheumatoid arthritis (RA) suggests a role for these cells in the pathogenesis of the disease. Recent evidence indicates that human T cells may fall into functional categories dependent on their cytokine profile and cytotoxic capacity. The human Th1 subset is cytolytic and produces high levels of IFN-gamma whereas the Th2 type of T cell produces IL-4. In order to investigate whether Th1 or Th2 type cells are present in the inflammatory synovial membrane in RA, a panel of synovial membrane derived T-cell clones (n = 19) was generated and studied functionally. Anti-CD3-induced cytotoxicity assays were performed to demonstrate the cytotoxic potential of clones. Except for two, all clones were cytolytic in this test. Clone cells were activated to initiate cytokine production and assessment of the cytokine levels showed that all clones produced large amounts of IFN-gamma (18 out of 19 clones: over 50,000 pg/ml) whereas IL-4 was absent or present in minimal amounts (17 out of 19 clones: less than 1000 pg/ml). The production of IL-1, IL-2 and IL-6 was variable. The functional characteristics of the clones studied indicate that they may resemble the Th1 subtype of T cells. Our data suggest a relation between Th1-type functions the chronic inflammation characteristic of RA.
 ...
PMID:T cells cloned from human rheumatoid synovial membrane functionally represent the Th1 subset. 134 69

Expression of vascular cell adhesion molecule-1 (VCAM-1) in synovial tissue was determined using the immunoperoxidase technique. Normal, rheumatoid arthritis (RA), and osteoarthritis (OA) synovia bound VCAM-1 antibodies in the intimal lining as well as blood vessels. The amount of VCAM-1 was significantly greater in the synovial lining of RA and OA tissues compared with normal synovium (p less than 0.002). There was also a trend toward greater levels of VCAM-1 staining in blood vessels of arthritic tissue (RA greater than OA greater than normal). Because VCAM-1 staining was especially intense in the synovial lining, VCAM-1 expression and regulation was studied on cultured fibroblast-like synoviocytes (FLS) derived from this region. Both VCAM-1 and intercellular adhesion molecule 1 were constitutively expressed on FLS. VCAM-1 expression was further increased by exposure to IL-1 beta, TNF-alpha, IL-4, and IFN-gamma. These cytokines (except for IL-4) also induced intercellular adhesion molecule 1 expression on FLS. ELAM was not detected on resting or cytokine-stimulated FLS. The specificity of VCAM-1 for FLS was demonstrated by the fact that only trace amounts were detected on normal and RA dermal fibroblasts. Cytokines induced intercellular adhesion molecule 1 display on dermal fibroblasts but had minimal effect on VCAM-1 expression. Finally, in adherence assays, Jurkat cell binding to resting FLS monolayers was inhibited by antibody to alpha 4/beta 1 integrin (VLA-4), CS-1 peptide from alternatively spliced fibronectin (which is another VLA-4 ligand), and, to a lesser extent, anti-VCAM-1 antibody. After cytokine stimulation of FLS, Jurkat-binding significantly increased, and this increase was blocked by anti-VCAM-1 antibody. Therefore, both CS-1 and VCAM-1 participate in VLA-4-mediated adherence to resting FLS in vitro, and VCAM-1 is responsible for the increase in Jurkat binding mediated by cytokines.
 ...
PMID:Alpha 4/beta 1 integrin (VLA-4) ligands in arthritis. Vascular cell adhesion molecule-1 expression in synovium and on fibroblast-like synoviocytes. 138 43

Both bacterial and mammalian heat shock proteins (HSP) are recognized by some T cells, and hsp60 recognition has been implicated in rheumatoid arthritis. We have developed a model to study the induction of hsp60 in human monocytic cell lines. An anti-mycobacterial hsp65 mAb (ML30), cross-reacting with human hsp60 was used to screen 21 human tumor cell lines in Western blot analysis. All T cell and B cell lymphomas constitutively expressed hsp60 protein at moderate to high levels, while little or no hsp60 protein was detected in two monocytic leukemia lines. Moderate to high levels of hsp60 mRNA and protein could be induced in the THP-I monocytic leukemia cell line by heat shock, retinoic acid, interferon (IFN)-gamma or tumor necrosis factor (TNF)-alpha treatment, the highest levels obtained with a combination of IFN-gamma/TNF-alpha. This was also seen using two rabbit anti-hsp60 antisera directed against the N-terminal or C-terminal part of the human hsp60 protein. The determinants detected by the ML30 mAb or the two rabbit anti-hsp60 antisera were not cell surface expressed, as measured with immunofluorescence (FACS) analysis on control cultured or cytokine treated cell lines. This could be a useful model for studies related to the induction of hsp60 in human cells.
 ...
PMID:Induction of human hsp60 expression in monocytic cell lines. 156 88

Monocyte recruitment and accumulation in the synovial tissue is pivotal in the evolution of rheumatoid arthritis (RA). In the present study we examined the chemotactic potential of monocytes obtained from synovial fluid (SF) of patients with RA. Functionally, SF monocytes exhibited greatly diminished chemotactic activity to C5a compared with monocytes from the peripheral blood. In contrast, their chemotactic responsiveness to the synthetic peptide, FMLP, was nearly normal. To define a mechanism for this differential chemotactic dysfunction, cell-surface receptors for C5a (C5aR) and FMLP (FMLP-R) were evaluated. Whereas FMLP-R expression was similar on both blood and inflammatory monocytes, C5aR expression was markedly reduced on SF cells. Because decreased C5a binding in certain RA SF samples could not be attributed to free C5a, known or suspected components of inflammatory SF were evaluated for their ability to modulate chemotactic ligand receptors. Bacterial products including LPS and streptococcal cell walls, which are potent monocyte activators, down-regulated C5aR without affecting FMLP-R. Moreover, the cytokines IFN-gamma and granulocyte-macrophage-CSF selectively decreased C5aR in parallel with decreased in vitro chemotactic activity to C5a. Thus, these data indicate that 1) synovial effusions may contain C5a and/or inflammatory mediators that modulate phenotypic and functional changes in monocytes, 2) chemotactic ligand receptors are independently regulated in inflammatory lesions, and 3) decreased C5aR expression and chemotactic potential likely provide a mechanism whereby monocyte-macrophages persist within the inflamed synovium.
 ...
PMID:Modulation of monocyte chemotactic function in inflammatory lesions. Role of inflammatory mediators. 189 61

The effects of GM-CSF, IL-2, IFN-gamma, TNF-alpha and IL-6 on the production of IL-1 (both secreted and cell associated) and TNF-alpha by peripheral blood monocytes were studied. Monocytes were cultured for 20 h in suspension and in serum-free conditions which minimized background stimulation of monokine production. GM-CSF, IL-2 and TNF-alpha directly induced the production of cell-associated IL-1 but little or no IL-1 or TNF-alpha secretion. Combination of GM-CSF with IFN-gamma, IL-2 or TNF-alpha synergistically enhanced IL-1 secretion and had an additive effect on cell-associated IL-1 production. Combination of IL-2 with IFN-gamma or TNF-alpha also synergistically enhanced IL-1 secretion but the effect on cell-associated IL-1 production was less than additive. GM-CSF synergistically enhanced TNF-alpha secretion induced by IFN-gamma but not by lipopolysaccharide. GM-CSF did not enhance TNF-alpha secretion induced by IL-2 or TNF-alpha. In contrast, IL-2 synergistically enhanced TNF-alpha secretion induced by IFN-gamma. These results are discussed in relation to cytokine involvement in rheumatoid arthritis.
 ...
PMID:Effects of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-2, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and IL-6 on the production of immunoreactive IL-1 and TNF-alpha by human monocytes. 190 83

Joints with rheumatoid arthritis are a site for chronic inflammation involving T cells, B cells, macrophages and dendritic cells. When these cells interact cytokines are likely to be produced. The presence of different cytokines in the synovial fluid of patients with rheumatoid arthritis has been studied and the macrophage derived cytokines such as IL-1, IL-6, TNF-alpha, TGF-beta and PDGF have usually been detected in large quantities, whereas T cell produced cytokines (IL-2, IL-4, IFN-gamma) are absent or present in small quantities. IL-1, IL-6 and TNF-alpha have several functions which suggest that they participate in the chronic disease process of rheumatoid arthritis, such as increasing production of eicosanoid, collagenase and prostaglandin E2. Many synovial B cells are activated and produce large amounts of immunoglobulins. We searched for a B cell stimulatory activity in rheumatoid synovial fluid and found a B cell differentiation and helper activity. Cytokines in the joints of patients with rheumatoid arthritis seem central for the propagation of the disease process. Specific intervention in cytokine production or in its effects might help to relieve symptoms in rheumatoid patients.
 ...
PMID:Cytokines in rheumatoid arthritis. 193 Sep 11

Granulocyte-macrophage CSF (GM-CSF) is a potent stimulator of macrophages and neutrophils and is produced by rheumatoid arthritis (RA) synovium. We now report studies that identify some of the synovial cells and cytokines responsible for local GM-CSF production and gene expression in RA. GM-CSF was assayed by ELISA in supernatants from cultured RA fibroblast-like synoviocytes stimulated with various cytokines (IL-1 beta, TNF-alpha, macrophage-CSF, IFN-gamma, IL-6, and TGF-beta). Immunoreactive GM-CSF was detected in IL-1 beta and TNF-alpha-stimulated cultures, but not in cells cultured in medium or stimulated with any of the other cytokines. IL-1 and TNF-alpha had a synergistic effect on GM-CSF production. GM-CSF gene expression by fibroblast-like synoviocytes was analyzed by ribonuclease protection assay, Northern blot analysis, and in situ hybridization. Both IL-1 beta and TNF-alpha induced GM-CSF mRNA accumulation, with a maximum effect after 4 h of stimulation. We then studied GM-CSF production by macrophage-like synoviocytes (MLS) isolated from fresh synovial specimens by flow microfluorimetry. Fresh MLS spontaneously secreted the cytokine and exogenous IL-1 beta or TNF-alpha had no effect. After 1 wk in culture, additional stimulation with IL-1 beta or TNF-alpha was required for GM-CSF production. Finally, in situ hybridization performed on freshly isolated subpopulations of synovial cells, identified GM-CSF RNA transcripts in MLS.
 ...
PMID:Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-alpha. 202 69

OM-89 is a bacterial extract from escherichia coli, proposed as an immunomodulating drug for the treatment of rheumatoid arthritis (RA). Since immunological mechanisms may play a role in its action, the immunological effects of OM-89 were evaluated in vitro on peripheral blood mononuclear cells (PBMC) derived from healthy subjects and RA patients. Results indicated that in the absence of OM-89, production of the monokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) is increased, while that of the lymphokines interleukin-2 (IL-2) and interferon-gamma (IFN-gamma is decreased by phytohemagglutinin (PHA)-stimulated PBMC from RA patients as compared with PBMC from healthy subjects. In the presence of PHA, OM-89 enhanced the production of IL-1 beta, TNF-alpha, IL-2, and IFN-gamma. IL-1 beta and IL-2 curves obtained using increasing amounts of OM-89 did not differ depending on the source of PBMC. By contrast, in the presence of increasing amounts of OM-89, TNF-alpha secretion significantly higher and IFN-gamma secretion significantly lower with PBMC from RA patients compared to PBMC from healthy subjects. These data indicate that OM-89 acts on monocytes and T cells directly and/or indirectly and suggest a possible clinical activity by OM-89 in RA relative to its immunological properties.
 ...
PMID:Effects of a hydrosoluble bacterial extract from Escherichia coli (OM-89) on cytokine production by peripheral blood mononuclear cells from healthy subjects and patients with rheumatoid arthritis. 206 42


1 2 3 4 5 6 7 8 9 10 Next >>