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)

Leflunomide is a pyrimidine biosynthesis inhibitor that has recently been approved for treatment of rheumatoid arthritis. However, the mechanism of leflunomide's antiarthritis activity and is not fully understood. The critical role that TNF plays in rheumatoid arthritis led us to postulate that leflunomide blocks TNF signaling. Previously, we have demonstrated that leflunomide inhibits TNF-induced NF-kappaB activation by suppressing I-kappaBalpha (inhibitory subunit of NF-kappaB) degradation. We in this study show that leflunomide also blocks NF-kappaB reporter gene expression induced by TNFR1, TNFR-associated factor 2, and NF-kappaB-inducing kinase (NIK), but not that activated by the p65 subunit of NF-kappaB, suggesting that leflunomide acts downstream of NIK. Leflunomide suppressed TNF-induced phosphorylation of I-kappaBalpha, as well as activation of I-kappaBalpha kinase-beta located downstream to NIK. Leflunomide also inhibited TNF-induced activation of AP-1 and the c-Jun N-terminal protein kinase activation. TNF-mediated cytotoxicity and caspase-induced poly(ADP-ribose) polymerase cleavage were also completely abrogated by treatment of Jurkat T cells with leflunomide. Leflunomide suppressed TNF-induced reactive oxygen intermediate generation and lipid peroxidation, which may explain most of its effects on TNF signaling. The suppressive effects of leflunomide on TNF signaling were completely reversible by uridine, indicating a critical role for pyrimidine biosynthesis in TNF-mediated cellular responses. Overall, our results suggest that suppression of TNF signaling is one of the possible mechanisms for inhibitory activity of leflunomide against rheumatoid arthritis.
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PMID:Leflunomide suppresses TNF-induced cellular responses: effects on NF-kappa B, activator protein-1, c-Jun N-terminal protein kinase, and apoptosis. 1106 59

The earlier known TNF family cytokines have fairly wide physiological actions, mainly in inflammation and immune responses. It is now considered feasible to develop these large proteins themselves as therapeutic agents, but in addition, modular organisation of structures of biological proteins, and the identification of localised ligand-receptor interaction sites, allow rational design of smaller, preferably nonpeptide molecules which interfere with these protein:protein interactions. Neutralising anti-TNF antibodies and soluble TNF receptor preparations were shown to have striking anti-inflammatory activities in clinical studies, particularly in rheumatoid arthritis. As the TNF beta:TNFR1 co-crystal structure was the first in the family to be solved, rational drug design based on the ligand:receptor interaction sites is more advanced. Ligand mutations and a peptide sequence from TNF-alpha have given useful information regarding ligand-receptor interactions. Small peptide sequences from TNFR I which interact with the ligand have shown some activity in blocking the biological actions of TNF. The physiological activities of several recently-discovered ligands are more limited, giving possibilities for selective treatment of several diseases. For example, TRAIL can induce apoptosis in a wide range of tumour cells with little effects on normal tissues, both in vitro and in vivo. The co-crystal structure of TRAIL with one of its signalling receptors TRAILR 2 has been solved, opening the way to rational small molecule drug design. TRANCE (RANKligand) has modulatory effects on the dendritic cell:T cell interaction in immune responses. However, it plays a more major controlling role in the development of osteoclasts and their bone resorbing activity. In this way, it is a very interesting drug development target for the treatment of bone disorders such as osteoporosis. A recombinant secreted inhibitory receptor, osteoprotegerin (OPG), is in Phase 1 clinical trial for the treatment of hyper-resorptive bone diseases. However, OPG also blocks TRAIL and may not be sufficiently specific in long term therapy, but it is hoped that inhibitors of the interaction of TRANCE and its specific signalling receptor, RANK, can be rationally designed.
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PMID:The use of TNF family ligands and receptors and agents which modify their interaction as therapeutic agents. 1146 75

Many insights have been gained into cytokine-regulated control of inflammatory processes and host defence in recent years. Evidence has also gradually accumulated that cytokine cascades play a central role in events regulating cell death and differentiation. Further developments include an understanding that the biological effects of the tumor necrosis factor-alpha (TNF-alpha or TNFSF) cytokine may be regulated by soluble TNF receptor binding and that modulation of receptor levels may permit physiological inhibition of TNF action. There has been a gradual realisation of the value of TNF/TNFR ratios as predictors of disease outcome, and the discovery of functional regulatory polymorphisms of the TNF gene and mutations of TNFRSF1A (TNFR1 receptor) have led to conceptual breakthroughs in our understanding of the genetic control of inflammation. However the exact mechanisms by which TNFRSF1A mutations give rise to disease susceptibility are not yet well understood. Over the past 10 years these concepts have been used as the basis for successful anti-TNF therapy of autoimmune diseases like rheumatoid arthritis (RA) and Crohn's disease.
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PMID:TNF and TNFR biology in health and disease. 1150 70

Although the etiology of rheumatoid arthritis (RA) has not been clearly understood to date, the hyperplasia of the synovial membrane imposed by pro-inflammatory cytokines has been suggested to play a crucial role in the progression of this disease. TNF-alpha, a potent pro-inflammatory cytokine, was detected at highly enhanced concentrations in the blood and synovial fluids of patients with RA relative to those of patients with osteoarthritis and normal subjects. To evaluate the role of TNF-alpha in the synovial hyperplasia during the pathogenic state, we investigated cellular outcomes and molecular mechanisms of synoviocytes in response to TNF-alpha. Following TNF-alpha treatment, fibroblast-like synoviocytes (FLS) obtained from patients with RA proliferated, unlike the cells from a normal subject that were unaffected. This TNF-alpha induced proliferation of synoviocytes obtained from RA patients coincided with down-regulation of TNFR1 and up-regulation of TNFR2 and TRAF1-6, as well as NF-kappaB activation. TNF-alpha-induced proliferation of synoviocytes was inhibited by transfection with a dominant negative mutant form of I-kappaBalpha cDNA (I-kappaBalphadN). Moreover, following TNF-alpha treatment, transfectants with I-kappaBalphadN underwent apoptosis, whereas mock-transfectants did not. Taken together, these results suggest that high levels of TNF-alpha present in RA synovium play an important role in the synovial hyperplasia of RA by suppressing apoptosis and promoting proliferation of synoviocytes through NF-kappaB-dependent signaling pathways mediated by up-regulated TNFR2 and TRAF1-6 molecules.
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PMID:Regulation of TNF-alpha-mediated hyperplasia through TNF receptors, TRAFs, and NF-kappaB in synoviocytes obtained from patients with rheumatoid arthritis. 1206 56

Tumor necrosis factor (TNF)-alpha is a pleiotropic cytokine involved in a broad spectrum of inflammatory and immune responses including proliferation, differentiation and cell death induction in several cell types. The biological effects of TNF-alpha are mediated via the cell-surface TNF receptors TNFR1 and TNFR2. Soluble forms of these two receptors, which contain the extracellular ectodomains, are proteolytically cleaved from the membrane. High levels of soluble (s) TNFR2 in serum have been documented in multiple inflammatory pathologies. We describe here a new differential spliced isoform of human TNFR2 missing exons 7 and 8, DS-TNFR2(Delta7,8). This novel isoform lacks the transmembrane and cytoplasmic domains. Expression studies with DS-TNFR2(Delta7,8) cDNA transiently transfected COS cells showed that it encodes a sTNFR2 receptor of approximately 42 kDa. Soluble DS-TNFR2(Delta7,8) blocked TNF-alpha-induced apoptosis, which suggests that it regulates TNF-alpha function by antagonizing its biological activity. An ELISA was developed that quantifies sTNFR2 generated by alternative splicing. Our data show that sTNFR2 generated by alternative splicing can be found in sera of healthy individuals, at increased levels in patients with sepsis and at high concentrations in rheumatoid arthritis patients.
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PMID:Identification and characterization of a novel spliced variant that encodes human soluble tumor necrosis factor receptor 2. 1468 72

Tumor necrosis factor-alpha (TNF-alpha)-induced signaling is pivotally involved in the pathogenesis of chronic inflammatory diseases. A polymorphism in the TNF receptor 2 (TNFR2) gene resulting in a juxtamembrane inversion from methionine (TNFR2(196MET)) to arginine (TNFR2(196ARG)) has been genetically associated with an increased risk for systemic lupus erythematosus and familial rheumatoid arthritis. Albeit the mutation does not affect the TNF binding kinetics of TNFR2, the present study provides evidence that the mutation results in a significantly lower capability to induce TNFR2-mediated NF-kappaB activation. Pretriggering of TNFR2 with a receptor-specific mutein leads to an enhancement of TNFR1-induced apoptosis, which is further increased in cells carrying the TNFR2(196ARG) variant. A diminished induction of NF-kappaB-dependent target genes conveying either anti-apoptotic or pro-inflammatory functions, such as cIAP1, TRAF1, IL-6, or IL-8 is observed. The mutated form TNFR2(196ARG) shows a reduction of inducible TRAF2 recruitment upon TNF-alpha stimulation. The findings suggest a common molecular mechanism for the involvement of the TNFR2(196ARG) variant in the etiopathogenesis of different chronic inflammatory disorders.
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PMID:The Met-196 -> Arg variation of human tumor necrosis factor receptor 2 (TNFR2) affects TNF-alpha-induced apoptosis by impaired NF-kappaB signaling and target gene expression. 1557 57

Therapies directed against tumour necrosis factor (TNF) are effective for the treatment of rheumatoid arthritis and reduce pain scores in this condition. In this study, we sought to explore mechanisms by which TNF contributes to inflammatory pain in an experimental model of arthritis. The effects of an anti-TNF agent, etanercept, on behavioural pain responses arising from rat monoarthritis induced by complete Freund's adjuvant were assessed and compared with expression of TNF receptors (TNFRs) by dorsal root ganglion (DRG) cells at corresponding time points. Etanercept had no effect on evoked pain responses in normal animals but exerted a differential effect on the thermal and mechanical hyperalgesia associated with rat arthritis induced by complete Freund's adjuvant (CFA). Joint inflammation was associated with increased TNFR1 and TNFR2 expression on DRG cells, which was maintained throughout the time course of the model. TNFR1 expression was increased in neuronal cells of the DRG bilaterally after arthritis induction. In contrast, TNFR2 expression occurred exclusively on non-neuronal cells of the macrophage-monocyte lineage, with cell numbers increasing in a TNF-dependent fashion during CFA-induced arthritis. A strong correlation was observed between numbers of macrophages and the development of mechanical hyperalgesia in CFA-induced arthritis. These results highlight the potential for TNF to play a vital role in inflammatory hyperalgesia, both by a direct action on neurons via TNFR1 and by facilitating the accumulation of macrophages in the DRG via a TNFR2-mediated pathway.
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PMID:The differential contribution of tumour necrosis factor to thermal and mechanical hyperalgesia during chronic inflammation. 1598 82

Tumour necrosis factor/cachecin (TNF-alpha) and lymphotoxin (LTalpha / TNF-alpha), 2 members of the TNF family of cytokines, have numerous biological functions, such as induction of apoptosis, cytotoxicity, inflammation, immunoregulation, proliferation and antiviral responses. Although TNF-alpha is produced by many cell types, the majority comes from activated macrophages. The related molecule, LT-alpha is produced mainly by activated lymphocytes and shares many of TNF's properties. TNF-alpha is active in both of its molecular forms, a secreted 17 kDa mature form and a transmembrane 26 kDa precursor. It induces activity by stimulating 2 distinct receptor subtypes, TNFR1 (55 kDa) and TNFR2 (75 kDa). The activation of TNFR1 is generally thought to trigger the majority of inflammatory and apoptotic effects, although TNFR2 has recently been shown to play more of a role in signal transduction than was initially thought. TNF-alpha is responsible for the induction of apoptosis in certain cell types, where it plays a pivotal role in the induction of cytotoxicity, killing of neoplastic cells and deletion of autoreactive T-cell clones. This cytokine, and in particular, its overproduction, has been implicated in the pathogenesis of a variety of immunologically mediated inflammatory diseases, including endotoxic shock, inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA). Currently, there is an intense effort underway to regulate TNF-alpha production and activity, in order to treat diseases where TNF-alpha is thought to be pathologically indicated. To achieve this goal, the pharmaceutical industry is currently pursuing a 2 pronged strategy: a) testing biological agents such as antibodies against TNF-alpha or soluble TNF-alpha receptor constructs, and b) identifying small molecular inhibitors directed against targets such as phosphodiesterase-IV (PDE-IV) and TNF-alpha converting enzyme (TACE), a subgroup of the matrix metalloproteinases (MMP). The main difficulties in the clinical implementation of the biological agents are: development of immunogenicity, lack of oral availability and the high cost of production. The currently available small molecular compounds exhibit poor bio-availability and low selectivity, resulting in unacceptable side effects and a low therapeutic index. Despite these hurdles, numerous companies are actively pursuing agents that inhibit TNF-alpha.
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PMID:AntiTNF-alpha agents in the treatment of inflammation. 1599 32

IL-12 and TNF-alpha are central proinflammatory cytokines produced by macrophages and dendritic cells. Disregulation of TNF-alpha is associated with sepsis and autoimmune diseases such as rheumatoid arthritis. However, new evidence suggests an anti-inflammatory role for TNF-alpha. TNF-alpha-treated murine macrophages produced less IL-12p70 and IL-23, after stimulation with IFN-gamma and LPS. Frequency of IL-12p40-producing macrophages correspondingly decreased as measured by intracellular cytokine staining. IL-12p40 production was also inhibited in dendritic cells. TNFR1 was established as the main receptor involved in IL-12p40 regulation, because IL-12p40 levels were not affected by TNF-alpha in TNFR1(-/-)-derived macrophages. Macrophages activated during Listeria monocytogenes infection were more susceptible to inhibition by TNF-alpha than cells from naive animals, which suggests a regulatory role for TNF-alpha in later stages of infection. This nonapoptotic anti-inflammatory regulation of IL-12 and IL-23 is an important addition to the multitude of TNF-alpha-induced responses determined by cell-specific receptor signaling.
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PMID:Paradoxical anti-inflammatory actions of TNF-alpha: inhibition of IL-12 and IL-23 via TNF receptor 1 in macrophages and dendritic cells. 1621 Jun 5

In common with many other cell types, synovial fibroblasts produce exosomes. In this study, we show that the exosomes produced by synovial fibroblasts obtained from individuals with rheumatoid arthritis (RASF), but not exosomes produced by synovial fibroblasts obtained from individuals with osteoarthritis, contain a membrane bound form of TNF-alpha as demonstrated by colloidal gold immunostaining of TNF-alpha and confirmed by both Western blot and mass spectrometry. The RASF-derived exosomes, but not exosomes derived from fibroblasts obtained from individuals with osteoarthritis, are cytotoxic for the L929 cell, a TNF-alpha-sensitive cell line, and stimulate activation of NF-kappaB and induction of collagenase-1 in RASF. These effects are blocked by addition of soluble TNFR1 (sTNFbp), suggesting that a TNF-alpha-signaling pathway mediates these biological activities. sTNFbp also reduced the production of exosomes by RASF, suggesting the interruption of a positive amplification loop. Exosomes can transmit signals between cells, and RASF exosomes, effectively taken up by anti-CD3-activated T cells, activated AKT and NF-kappaB and rendered these activated T cells resistant to apoptosis. Neutralization of exosomal membrane TNF-alpha by sTNFbp partially reversed this resistance, suggesting that not only TNF-alpha but also additional exosomal proteins may contribute to the development of apoptosis resistance.
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PMID:A membrane form of TNF-alpha presented by exosomes delays T cell activation-induced cell death. 1675 83


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