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)

The majority of synovial fluids from 29 rheumatoid arthritis patients were strongly attractive for normal blood lymphocytes judged by assays of polarization and collagen gel invasion. While rheumatoid synovial fluids contained IL-15, IL-8, monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) at levels sufficient to attract lymphocytes, inhibition of the activity of any single cytokine using specific antibody did not abolish the activity of the fluid. However combinations of anti-cytokine antibodies used together (anti-IL-15+anti-MCP-1; anti-IL-8+anti-MCP-1 or +anti-MIP-1 alpha) inhibited most of the activity, suggesting that attraction of lymphocytes by the fluids is due to a combination of attractants. Blood lymphocytes required activation by overnight culture to respond optimally, while rheumatoid synovial tissue lymphocytes responded to synovial fluids without a requirement for a period of culture. Lymphocytes derived from rheumatoid synovial fluids were poorly responsive to locomotor stimulants. Most of the responding cells from blood mononuclear cell fractions were T lymphocytes of the CD45RO isotype. Incubation in the presence of cyclosporin A or corticosteroids inhibited the response of lymphocytes to the fluids, but the presence of non-steroidal anti-inflammatory drugs (NSAIDs) and other agents used in therapy of the patients from whom the fluids were taken had no inhibitory effect.
 ...
PMID:The chemoattractant activity of rheumatoid synovial fluid for human lymphocytes is due to multiple cytokines. 891 67

Tumor necrosis factor-alpha occupies a central role in rheumatoid arthritis (RA) pathogenesis. We now report that interleukin-15 (IL-15) can induce TNF-alpha production in RA through activation of synovial T cells. Peripheral blood (PB) T cells activated by IL-15 induced significant TNF-alpha production by macrophages via a cell-contact-dependent mechanism. Freshly isolated RA synovial T cells possessed similar capability, and in vitro, IL-15 was necessary to maintain this activity. IL-15 also induced direct TNF-alpha production by synovial T cells. In contrast, IL-2 induced significantly lower TNF-alpha production in either cell-contact-dependent or direct culture, and IL-8 and MIP-1 alpha were ineffective. Antibodies against CD69, LFA-1 or ICAM-1 significantly inhibited the ability of T cells to activate macrophages by cell contact.
 ...
PMID:Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis. 962 50

Low expression of CD45RB on CD45RO+ T lymphocytes defines a subset of highly differentiated T lymphocytes that accumulate in vivo within the affected joints of patients with rheumatoid arthritis (RA). Although it is known that CD45RO+ T lymphocytes migrate to sites of inflammation in vivo, it is not clear whether within this subset the CD45RBlo cells are selectively recruited or develop in situ within the joint. Using a transwell system we show that a small proportion of resting T lymphocytes migrated across unactivated human umbilical vein endothelial cells (HUVEC). These migrating cells were CD45RO+ and enriched for low CD45RB expression. In addition, both the CD45RO+CD45RBlo subset and migrating cells expressed increased levels of beta 1 and beta 2 integrins and CD44. The percentage of CD45RO+CD45RBlo T lymphocytes was increased in the circulation of patients with acute Epstein-Barr virus (EBV) infection. These in vivo activated cells also expressed increased levels beta 1 and beta 2 integrins and CD44, and showed an enhanced rate of transmigration compared with resting T lymphocytes. Transmigration of T lymphocytes was increased using the chemokines RANTES and lymphotactin and the cytokine interleukin-15 (IL-15). In addition, infection of the HUVEC with cytomegalovirus (CMV) led to an enhanced movement of T lymphocytes. In all of these cases the selective migration of the CD45RBlo subset was maintained. Thus although the rate of T-lymphocyte transmigration could be influenced by a number factors, the CD45RO+CD45RBlo subset has a migratory advantage suggesting that more differentiated CD45RO+CD45RBlo T lymphocytes are selectively recruited to sites of inflammation.
 ...
PMID:Selective migration of highly differentiated primed T cells, defined by low expression of CD45RB, across human umbilical vein endothelial cells: effects of viral infection on transmigration. 913 57

It has been reported that the mRNA of the type 1 cytokine, interferon-gamma (IFN-gamma)--but not the type 2 cytokine interleukin-4 (IL-4)--is detected in synovial tissues of rheumatoid arthritis (RA) patients, whereas both IFN-gamma and IL-4 mRNA are detected in reactive arthritis (ReA). To evaluate such data more extensively, we obtained 208 synovial specimens in a prospective study of 52 early synovitis patients (13 RA, 11 ReA, 28 undifferentiated oligoarthropathy) and analyzed type 1 and type 2 cytokine mRNA expression in specimens containing sufficient mRNA. Using a nested reverse transcriptase polymerase chain reaction technique, we measured the relative mRNA levels of 10 cytokines and CD3 delta chain. We detected IL-10, IL-15, and CD3 delta chain mRNA in all RA and ReA patients and frequently detected tumor necrosis factor-alpha, IL-1 beta, and IFN-gamma mRNA. IL-6 and IL-12 p40 mRNA were detected in approximately one-half of the patients. We also detected greater amounts of IL-2 and IFN-gamma mRNA in ReA than were detected in RA. However, we rarely detected IL-4 or IL-13 mRNA. Similar cytokine profiles were observed in undifferentiated oligoarthropathy. The amounts of cytokine mRNAs, except for IL-10, in specimens from the patients taking prednisone or second-line antirheumatic drugs tended to be less than in specimens from the patients taking neither prednisone nor second-line antirheumatic drugs. These results suggest that cytokine mRNA profiles in patients with RA, ReA, and undifferentiated arthritis in their early stages are skewed toward proinflammatory macrophage-derived and type 1 cytokines. IL-10--not IL-4 or IL-13--mRNA appears to be the major antiinflammatory cytokine mRNA. Drug therapy is associated with depressed proinflammatory and type 1 cytokine mRNA production. The differences in the expression of IL-2 and IFN-gamma mRNA between RA and ReA may reflect unique etiological or host factors associated with the early stages of these diseases.
 ...
PMID:In vivo gene expression of type 1 and type 2 cytokines in synovial tissues from patients in early stages of rheumatoid, reactive, and undifferentiated arthritis. 915 45

Recently, a new player in the cytokine network has been described that is produced by monocytes and can be detected in the rheumatoid synovium: interleukin-15 (IL-15). Since this cytokine may play a role in the accumulation and activation of T-cells, B-cells, and natural killer (NK) cells characteristic of synovial tissue (ST) from patients with rheumatoid arthritis (RA), the expression of IL-15 was studied in ST from RA patients in comparison with ST from patients with reactive arthritis (ReA) and osteoarthritis (OA) and the phenotype of IL-15-positive cells was determined. IL-15 expression was investigated by immunohistochemical analysis of ST from ten patients with RA, ten patients with Yersinia enterocolitica-induced ReA, and nine patients with OA. The immunohistological findings were quantified and the results obtained in the different patient groups were compared. To determine the phenotype of IL-15-expressing cells, double-labelling immunofluorescence was performed. The expression of IL-15 was significantly higher in ST from patients with RA than in ST from patients with ReA or OA. In double-label experiments, co-expression was observed with markers for macrophages, T-cells, and NK cells. The composition of the cellular infiltrate in the synovium of patients with RA might be partly explained by the specific increase in expression of IL-15 in rheumatoid ST. It can be speculated that IL-15 production by inflammatory cells other than macrophages may occur in the rheumatoid synovium.
 ...
PMID:Increased expression of IL-15 in the synovium of patients with rheumatoid arthritis compared with patients with Yersinia-induced arthritis and osteoarthritis. 919 44

The capacity of endothelial cells (EC) to produce IL-15 and the capacity of IL-15 to influence transendothelial migration of T cells was examined. Human umbilical vein endothelial cells expressed both IL-15 mRNA and protein. Moreover, endothelial-derived IL-15 enhanced transendothelial migration of T cells as evidenced by the inhibition of this process by blocking monoclonal antibodies to IL-15. IL-15 enhanced transendothelial migration of T cells by activating the binding capacity of the integrin adhesion molecule LFA-1 (CD11a/CD18) and also increased T cell motility. In addition, IL-15 induced expression of the early activation molecule CD69. The importance of IL-15 in regulating migration of T cells in vivo was documented by its capacity to enhance accumulation of adoptively transferred human T cells in rheumatoid arthritis synovial tissue engrafted into immune deficient SCID mice. These results demonstrate that EC produce IL-15 and imply that endothelial IL-15 plays a critical role in stimulation of T cells to extravasate into inflammatory tissue.
 ...
PMID:Interleukin 15 is produced by endothelial cells and increases the transendothelial migration of T cells In vitro and in the SCID mouse-human rheumatoid arthritis model In vivo. 950 67

In rheumatoid arthritis (RA), T cells in the inflamed joint are considered to play a crucial role in the pathogenesis. However, despite the fact that synovial T cells have an activated memory phenotype, they are functionally suppressed upon combined CD3 and CD28 stimulation. Here, we analyzed the contribution of both CD3 and CD28 to the hyporesponsiveness of synovial T cells in RA. In contrast to the low CD3 responsiveness of synovial fluid (SF) T cells compared to peripheral blood (PB) T cells, the CD28 co-stimulatory response was observed to be unaffected. Hyporesponsiveness of SF T cells has previously been associated with decreased levels of intracellular glutathione (GSH), an antioxidant and regulator of the intracellular redox state. Treatment of SF T cells with N-acetylcysteine, an antioxidant and replenisher of GSH, selectively improved CD3-induced responses, while leaving CD28 responsiveness unaffected. These data show that the CD3 pathway is highly sensitive to intracellular GSH alterations, whereas CD28 responsiveness is relatively refractory. Furthermore, in support for a functional role of CD28 co-stimulation, it was demonstrated that CD28 ligation acted in synergy with the IL-2 receptor gamma chain signaling cytokine IL-15 in the enhancement of the ex vivo survival of SF T cells. These data indicate that CD28 co-stimulatory capacity of SF T cells, in contrast to CD3 stimulation, remains intact despite an altered intracellular redox state. Thereby, CD28 stimulation may contribute to the persistence of T cells at the site of inflammation, which might be of relevance in the pathogenesis of RA.
 ...
PMID:CD28 co-stimulation is intact and contributes to prolonged ex vivo survival of hyporesponsive synovial fluid T cells in rheumatoid arthritis. 960 60

IL-15 has recently been detected in the synovium of patients with rheumatoid arthritis. IL-15-activated T cells induce significant TNF-alpha synthesis by macrophages via a cell contact-dependent mechanism, suggesting a key regulatory role for IL-15. Here, we report that the administration of a soluble fragment of IL-15Ralpha into DBA/1 mice, profoundly suppressed the development of collagen-induced arthritis. This was accompanied in vitro by marked reductions in Ag-specific proliferation and IFN-gamma synthesis by spleen cells from treated mice compared with control mice and in vivo by a significant reduction in serum anti-collagen Ab levels. These data directly demonstrate a pivotal role for IL-15 in the development of inflammatory arthritis and also suggest that antagonists to IL-15 may have therapeutic potential in rheumatic diseases.
 ...
PMID:Soluble IL-15 receptor alpha-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology. 960 72

This review focuses on the biological effects of the newly discovered cytokine, interleukin 15 (IL-15), in chronic inflammatory disorders. IL-15 shares biological activities with IL-2, and like IL-2 it is a member of the four-helix bundle cytokine family. IL-15 interacts with a heterotrimeric receptor that consists of the beta and gamma subunits of the IL-2 receptor (IL-2R) as well as a specific, high-affinity IL-15-binding subunit, IL-1SRalpha. IL-15 is produced by macrophages and various other cells in response to environmental stimuli and infectious agents, and it is important for the growth and differentiation of T and B lymphocytes, natural killer cells, macrophages, and monocytes as well as it activates a number of important intracellular signaling molecules, including the Janus kinases and members of the transcription factor family of signal transducers and activators of transcription. These facts suggest that IL- 15 may play a pivotal role both in protective immune responses and in the pathogenesis of various chronic immuno-inflammatory disorders. The important new insight into the role of IL-15 in diseases such as rheumatoid arthritis, sarcoidosis, chronic hepatitis C, and ulcerative colitis are reviewed in this paper.
 ...
PMID:Interleukin-15 and its role in chronic inflammatory diseases. 971 92

In rheumatoid arthritis, T lymphocytes have been proposed to play a pivotal role in the disease process, but they have also been considered to simply represent an epiphenomenon in a primarily synoviocyte/macrophage-driven disease. To directly examine the contribution of CD4 T cells in synovitis, T cells were either depleted from or adoptively transferred into NOD-SCID mice engrafted with rheumatoid synovial tissue. Injection of anti-CD2 antibody resulted in the elimination of 80-90% of tissue-infiltrating T cells in the synovial grafts and was followed by a marked decline in the production of IL-1beta (loss of 70%), TNF-alpha (loss of 86%), and IL-15 (loss of 84%) mRNA. Also, transcription of MMP-1 and MMP-2 was reduced by 72% in anti-CD2-treated chimeras. Immunohistochemistry demonstrated that the cytokines and proteases derived mostly from CD68(+) synovial cells, which disappeared from the tissue upon T cell depletion. Adoptive transfer of autologous tissue-derived T cell lines and T cell clones into synovium-SCID mouse chimeras augmented the production of IFN-gamma as well as TNF-alpha in the synovial infiltrates. Administration of IFN-gamma in small doses to anti-CD2-treated chimeras restored the survival and the functional activity of CD68(+) synovial cells. In vitro studies confirmed the critical role of synovial T cells and IFN-gamma in the survival of synovial CD68(+) cells. These data demonstrate that the production of proinflammatory cytokines and of tissue-degrading enzymes in rheumatoid synovitis is T cell dependent and that CD4 T cells are primary regulatory cells in this disease.
 ...
PMID:Production of cytokines and metalloproteinases in rheumatoid synovitis is T cell dependent. 988 54


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