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)

To investigate the role of the CD40-CD154 interaction in rheumatoid arthritis (RA), we analysed the expression of CD154 on CD3+ and CD4+ T cells in synovial fluid (SF) from patients with RA and in peripheral blood (PB) from patients and normal controls. As interleukin (IL)-15 is a potent activator of synovial T cells we wanted to study whether IL-15 also regulated the expression of CD154 on these T cells. Freshly isolated synovial T cells did not express significant levels of CD154, as evaluated using flow cytometry, whereas the expression of CD86 and human leucocyte antigen (HLA)-DR was significantly elevated on SF T cells when compared with PB T cells from patients or controls. Synovial T cells could up-regulate their CD154 expression following activation with phorbol 12-myristate 13-acetate (PMA) + ionomycin or anti-CD3 + anti-CD28 monoclonal antibodies (mAbs), but the maximal level of expression remained lower than in control T cells. IL-15 significantly increased the expression of CD154 on SF and PB T cells from patients, whereas IL-2 had minimal effects. Furthermore, IL-15 induced extensive proliferation in SF T cells. Our results show that SF T cells up-regulate the expression of CD154 in the presence of IL-15, a cytokine present in the synovium of patients with RA. These results further emphasize the role of IL-15 in the pathogenesis of RA.
 ...
PMID:Interleukin-15 up-regulates the expression of CD154 on synovial fluid T cells. 1088 1

Rheumatoid arthritis (RA) is characterized by the accumulation of CD4(+) memory T cells in the inflamed synovium. To address the mechanism, we analyzed chemokine receptor expression and found that the frequency of CXC chemokine receptor (CXCR)4 expressing synovial tissue CD4(+) memory T cells was significantly elevated. CXCR4 expression could be enhanced by IL-15, whereas stromal cell-derived factor (SDF)-1, the ligand of CXCR4, was expressed in the RA synovium and could be increased by CD40 stimulation. SDF-1 stimulated migration of rheumatoid synovial T cells and also inhibited activation-induced apoptosis of T cells. These results indicate that SDF-1-CXCR4 interactions play important roles in CD4(+) memory T cell accumulation in the RA synovium, and emphasize the role of stromal cells in regulating rheumatoid inflammation.
 ...
PMID:Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. 1108 3

The intricate interactions that regulate relationships between endogenous tissue cells and infiltrating immune cells in the rheumatic joint, particularly in rheumatoid arthritis (RA), were the subject of the meeting. A better understanding of these interactions might help to define intervention points that could be used to develop specific therapies. The presentations and discussions highlighted the fact that, once chronic inflammation is established, several proinflammatory loops involv9ing tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta can be defined. Direct cellular contact with stimulated T lymphocytes induces TNF-alpha and IL-1beta in monocytes which in turn induce functions in fibroblast-like synoviocytes. The latter include the production of stromal cell-derived factor-1alpha (SDF-1alpha) which enhances the expression of CD40L in T cells, which stimulates SDF-1alpha production in synoviocytes, which in turn protects T and B cells from apoptosis and enhances cell recruitment thus favoring inflammatory processes. IL-1beta and TNF-alpha also induce IL-15 in fibroblast like synoviocytes, which induces the production of IL-17 which in turn potentiates IL-1beta and TNF-alpha production in monocyte-macrophages. This underlies the importance of TNF-alpha and IL-1beta in RA pathogenesis, and helps explain the efficiency of agents blocking the activity of these cytokines in RA. Factors able to block the induction of cytokine production (such as apolipoprotein A-I [apo A-I] and interferon [IFN]-beta) might interfere more distally in the inflammatory process. Furthermore, stimulated T lymphocytes produce osteoclast differentiation factor (ODF), which triggers erosive functions of osteoclasts. Therefore, factors capable of affecting the level of T lymphocyte activation, such as IFN-beta, IL-15 antagonist, or SDF-1alpha antagonist, might be of interest in RA therapy.
 ...
PMID:Cell contact interactions in rheumatology, The Kennedy Institute for Rheumatology, London, UK, 1-2 June 2000. 1121 94

IL-15 is a pleiotropic cytokine that plays important roles in both innate and adaptive immunity. It is associated with a range of immunopathology, including rheumatoid arthritis and allograft rejection. IL-15 functions through the trimeric IL-15R complex, which consists of a high affinity binding alpha-chain and the common IL-2R beta- and gamma-chains. Characterization of IL-15/IL-15R interactions may facilitate the development of improved IL-15 antagonists for therapeutic interventions. We previously constructed soluble murine IL-15Ralpha (sIL-15Ralpha) by deleting the cytoplasmic and transmembrane domains. To localize the functional domain of IL-15Ralpha, we have now constructed various truncated versions of sIL-15Ralpha. The shortest region retaining IL-15 binding activity is a 65-aa sequence spanning the Sushi domain of IL-15Ralpha. Sushi domains, common motifs in protein-protein interactions, contain four cysteines forming two disulfide bonds in a 1-3 and 2-4 pattern. Amino acid substitution of the first or fourth cysteine in sIL-15Ralpha completely abolished its IL-15 binding activity. This also abrogated the ability of sIL-15Ralpha to neutralize IL-15-induced proinflammatory cytokine production and anti-apoptotic response in vitro. Furthermore, the mutant sIL-15Ralpha lost its ability to inhibit carrageenan-induced local inflammation and allogenic cell-induced T cell proliferation and cytokine production in vivo. Thus, the Sushi domain is critical for the functional activity of sIL-15Ralpha.
 ...
PMID:The Sushi domain of soluble IL-15 receptor alpha is essential for binding IL-15 and inhibiting inflammatory and allogenic responses in vitro and in vivo. 1141 60

Advances in the understanding of the pathogenesis of rheumatoid arthritis (RA) as well as improved biotechnology has enabled selective targeting of the pathogenic elements of disease. Targeting cell recruitment through adhesion molecules has been shown to be successful in pre-clinical murine models. Results of studies of an anti-ICAM-1 monoclonal antibody and anti-sense oligonucleotides have been encouraging. An alternate approach to inhibiting recruitment has been the targeting of chemoattractant molecules ie. chemokines. Important advances have been made in cytokine directed therapy targeting TNFalpha and IL-1. TNF antagonists (anti-TNF monoclonal antibody/soluble TNF receptor Fc fusion protein) have resulted in rapid and substantial improvement in signs and symptoms of disease as well as disease modification, shown by slowing of radiological progression. IL-1 receptor antagonist protein appears to have a significant effect on radiological progression despite a modest effect on symptoms and signs. Studies using anti-inflammatory cytokines such as IL-10 are in progress. A more recent therapeutic approach has been to target T-cell activation by interfering with co-stimulatory complexes such as CD40L/CD40 and CD28/CD80 and CD86. Both pre-clinical and preliminary clinical studies in human subjects support the concept. Another approach involving T-cell receptor peptide vaccination with VB peptides over-utilized in RA synovium has shown to be beneficial. Targeting the cytokines driving T-cells in the RA synovium ie. IL-12 & IL-15 has also proven beneficial in animal studies. Recent attention has also been directed toward the invading synovial fibroblast using Fas-FasL mediated apoptosis. Pre-clinical studies in which angiogenesis and osteoclast activation are targeted have been encouraging. In conclusion, the proof of principle has been established that selective targeting of pathogenic elements of disease results in substantial improvement in signs and symptoms as well as disease progression. Improved efficacy is expected with more aggressive targeting of the pathogenic elements.
 ...
PMID:Biologic agents in the treatment of rheumatoid arthritis. 1146 81

CD26, a transmembrane ectoenzyme, is overexpressed on rheumatoid arthritis (RA) peripheral blood T cells. As it has been recently described that IL-12 and IL-15 upregulate CD26 in vitro, we hypothesized that this CD26 overexpression might be interleukin dependent. The concentrations of IL-12 and IL-15, and soluble CD26 and adenosine deaminase (enzymes related to CD26) were analyzed in the serum of 35 patients with active and inactive RA and of healthy control subjects. IL-12 and IL-15 levels were significantly higher in patients' serum, independently of disease activity, even in patients on steroid therapy, i.e., the present therapies cannot eradicate their origin. Soluble CD26 was significantly reduced and related to the disease activity. In particular, it correlated inversely with the number of swollen joints. Although these data did not support our hypothesis, they support that interleukins not only initiate RA pathology but they can also participate in the maintenance of this immune response.
 ...
PMID:Serum interleukin-12, interleukin-15, soluble CD26, and adenosine deaminase in patients with rheumatoid arthritis. 1173 62

We attempted to determine whether various cytokine levels in the serum and synovial fluid (SF) of rheumatoid arthritis (RA) patients are influenced by the performance of filtration leukocytapheresis (LCP). The filtration LCP procedure that used a Cellsorba column (LCP group: n=22; responder subgroup: n=17, non-responder subgroup: n=5) or sham apheresis (control group; n=7) was repeated three times at 1-week intervals. Serum (LCP group, n=22; control group, n=7) and SF (LCP group, n=6; control group, n=3) samples were collected before and after LCP. Levels of tumor necrosis factor alpha (TNFalpha), interleukins (IL-1 beta, IL-2, IL-6, IL-8, IL-10, and IL-15), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), RANTES were measured by an enzyme-linked immunosorbent assay. Serum TNF alpha, IL-15, and RANTES were significantly reduced only in the LCP group. Serum IL-10 significantly increased only in the LCP group. In the LCP subgroup, serum IL-15, GM-CSF, and RANTES levels were reduced significantly, while serum IL-10 levels increased significantly only in the responder group after treatment. Serum TNF alpha levels were reduced significantly in both subgroups. Changes in serum IL-10 correlated positively with the improvement of patient's assessment of pain and global severity, and physician's assessment of global severity. These results indicate that the removal of leukocytes from the peripheral blood of RA patients provokes dynamic changes in some cytokine levels in the serum and/or synovial fluid. These changes may explain some of the mechanisms by which the articular symptoms are improved by filtration LCP.
 ...
PMID:Dynamic changes in cytokine levels in serum and synovial fluid following filtration leukocytapheresis therapy in patients with rheumatoid arthritis. 1174 32

Among potential targets for nonspecific anti-inflammatory immunointervention, three pro-inflammatory interleukins (ILs) have recently been found to play a pivotal role in rheumatoid arthritis (RA). IL-15 has both chemoattractant and proinflammatory properties and may promote bone destruction. IL-17, a product of T lymphocytes, has proinflammatory effects and induces production of metalloproteinases such as MMP-1. IL-18 not only has proinflammatory, angiogenic, and chemoattractant effects but also promotes cartilage destruction. These cytokines are potential targets for specific or nonspecific anti-inflammatory therapy. Thus, blocking IL-15 by its receptor reduces the severity of experimental collagen-induced arthritis (CIA). In this model, IL-17 levels fall after administration of anti-inflammatory cytokines such as IL-4 or IL-13. Finally, monoclonal anti-IL-18 antibodies prevent streptococcal cell wall arthritis, and IL-18 binding protein, which is a naturally occurring IL-18 inhibitor, prevents CIA.
 ...
PMID:Novel pro-inflammatory interleukins: potential therapeutic targets in rheumatoid arthritis. 1180 83

Constitutive mRNA expression and secretion of proinflammatory and anti-inflammatory cytokines was comparatively analyzed in rheumatoid arthritis (RA) synovial fibroblasts (SFB), isolated from primary culture or derived by repeated passage; normal-skin fibroblasts were used as controls. First-passage RA-SFB (n = 3) secreted large amounts of IL-6 (15,800 +/- 2,110 pg/ml; mean +/- SEM), but only limited amounts of tumor necrosis factor (TNF)-alpha (22.1 +/- 1.1 pg/ml) or IL-10 (35.7 +/- 34.2 pg/ml; only one of three samples was positive). IL-1beta, IL-15, and IL-18 were not detectable at the protein level and showed very low mRNA levels by semiquantitative RT-PCR. In repeated-passage RA-SFB (tenth passage), protein secretion was significantly lower for IL-6 (one-twentieth of the initial level) and TNF-alpha (two-thirds), and markedly reduced for IL-10 (one-quarter, with only one of three samples positive). While the decrease of IL-10 protein from first to tenth passage was paralleled by a corresponding decrease of mRNA, the relative mRNA levels for IL-6 and TNF-alpha were actually increased (20-fold and 300-fold, respectively), indicating post-transcriptional and/or post-translational regulation of these cytokines. Due to highly variable levels among individual patients, however, no significant differences were observed for any cytokine mRNA between primary-culture and repeated-passage RA-SFB (ninth passage). Likewise, no significant differences were detectable between RA-SFB and normal-skin fibroblasts (primary-culture and repeated-passage). By producing high amounts of IL-6 and limited amounts of TNF-alpha, RA-SFB may contribute to the (im)balance of proinflammatory and anti-inflammatory cytokines in the inflamed joint.
 ...
PMID:Cytokine mRNA and protein expression in primary-culture and repeated-passage synovial fibroblasts from patients with rheumatoid arthritis. 1187 47

The hallmarks of rheumatoid arthritis (RA) are leukocytic infiltration of the synovium and expansiveness of fibroblast-like synoviocytes (FLS). The abnormal proliferation of FLS and their resistance to apoptosis is mediated, at least in part, by present in RA joints proinflammatory cytokines and growth factors. Because IL-15 exerts properties of antiapoptotic and growth factors, and is produced by RA FLS, we hypothesized that IL-15 participates in RA FLS activation. To test this hypothesis, we first examined whether RA FLS express chains required for high affinity functional IL-15R. Indeed, RA FLS express IL-15Ralpha at mRNA and protein levels. Moreover, we confirmed the presence of IL-2Rbeta and common gamma-chains. Interestingly, TNF-alpha or IL-1beta triggered significant elevation of IL-15Ralpha chain at mRNA and protein levels. Next, we investigated the effects of exogenous or endogenous IL-15 on Bcl-2 and Bcl-x(L) expression, FLS proliferation, and apoptosis. Exogenous IL-15 enhanced RA FLS proliferation and increased the level of mRNA-encoding Bcl-x(L). To test the role of endogenous IL-15 in the activation of RA FLS, an IL-15 mutant/Fcgamma2a protein exerting properties of specific antagonist to the IL-15Ralpha chain was used. We found that blocking IL-15 biological activities using this protein substantially reduced endogenous expression of Bcl-2 and Bcl-x(L), and RA FLS proliferation that was reflected by increased apoptosis. Thus, we have demonstrated that a distinctive phenotype of RA FLS, i.e., persistent activation, proliferation, and resistance to apoptosis, is related to the autocrine activation of IL-15Rs by FLS-derived IL-15.
 ...
PMID:Fibroblast-like synoviocytes from rheumatoid arthritis patients express functional IL-15 receptor complex: endogenous IL-15 in autocrine fashion enhances cell proliferation and expression of Bcl-x(L) and Bcl-2. 1216 97


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