Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TSG-6 is an arthritis-associated hyaluronan binding protein whose production in synovial cells, chondrocytes, fibroblasts and mononuclear cells is stimulated by TNF-alpha and IL-1. The purpose of this study was to gain insights into the role of TSG-6 and its functional interactions with hyaluronan in inflammation. In the murine air pouch model of carrageenan/IL-1-induced inflammation TSG-6 showed a dramatic inhibitory effect on the cellular infiltration of the inflammatory site by neutrophilic PMN, while hyaluronan enhanced cellular infiltration. There was no indication of a neutralizing or cooperative effect when TSG-6 and hyaluronan were injected together. The potent antiinflammatory effect of TSG-6 along with its induction by proinflammatory cytokines suggests that TSG-6 is part of a negative feedback loop in the control of the inflammatory response.
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PMID:TSG-6, a glycoprotein associated with arthritis, and its ligand hyaluronan exert opposite effects in a murine model of inflammation. 873 46

We have used fas-defective MRL-lpr/lpr mice to study the effects of the staphylococcal enterotoxin superantigens on the development of autoimmune, inflammatory joint disease in animals that are susceptible to the development of rheumatoid arthritis-like disease. We show that systematic administration by a single i.p. injection of staphylococcal enterotoxin B (SEB; 10 micrograms/mouse) caused a mild, inflammatory arthritis +30 days postchallenge in the knee joints of young (< 2-mo-old) MRL-lpr/lpr mice, but not aged-matched MRL +/+ mice. In aged (> 8-mo-old) MRL-lpr/lpr mice, but not in aged MRL +/+ mice, SEB caused a severe, inflammatory arthritis, as assessed histologically, and systemic autoimmune disease, including glomerulonephritis and autoantibody production. Furthermore, in aged MRL-lpr/lpr mice, SEB but not heat-denatured SEB caused acute weight loss and elevated levels of serum proinflammatory cytokines. Compared with highly purified peritoneal macrophages obtained from either aged MRL +/+, young MRL-lpr/lpr, or young MRL +/+, peritoneal macrophages obtained from aged MRL-lpr/lpr mice constitutively expressed 2- to 10-fold greater levels of TNF-alpha, IL-1 beta, IL-6, and IL-10, and produced elevated amounts of these cytokines when treated in vitro with SEB. SEB-challenged aged MRL-lpr/lpr mice treated with anti-TNF mAb (100 micrograms/mouse; every other day), anti-V beta 8 TCR mAb (250 micrograms/mouse; every other day), or orally with the novel TNF-alpha inhibitor MDL 201,449A (9-[(1R, 3R)-trans-cyclopentan-3-ol] adenine; 25 mg/kg/day) exhibited reduced inflammatory arthritis, autoantibody formation, and serum TNF-alpha levels, but not IL-10 levels, after +30 days of treatment. These data suggest that SEB is an extremely potent macrophage-activating factor in vitro and in vivo, enhancing several aspects of autoimmune disease in MRL-lpr/lpr mice, and that anti-TNF therapies may have potential use in inflammatory arthritis.
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PMID:Inhibition of superantigen-induced proinflammatory cytokine production and inflammatory arthritis in MRL-lpr/lpr mice by a transcriptional inhibitor of TNF-alpha. 875 66

It is hypothesized that the balance of cytokines produced by Th1/Th2 subsets of T helper cells plays an important role in the development of autoimmune diseases. Murine collagen-induced arthritis (CIA) is an example of an autoimmune disease in which immunization with cartilage-derived type II collagen induces, firstly, a T cell response to type II collagen and, secondly, the manifestation of a destructive inflammatory response in affected joints. We have investigated the role of Th1/Th2 responses in the development of CIA by monitoring levels of interferon (IFN)-gamma (a Th1 cytokine) and interleukin (IL)-4 and IL-10 (Th2 cytokines), and IL-1 beta and tumor necrosis factor (TNF) (pro-inflammatory cytokines) produced by cultured draining lymph node cells (LNC) from collagen-immunized DBA/1 mice during the induction phase of arthritis and throughout the time of clinical manifestation and subsequent remission of the disease. Although a transient increase in IL-10 was detected 3 days after immunization, Th2 cytokine production was found to be almost completely suppressed 6 days after immunization. In contrast, IFN-gamma was detected in LNC cultures as early as 6 days after immunization and the addition of type II collagen to the culture medium resulted in an approximately 10-fold increase in IFN-gamma production, indicating that a predominantly Th1 response had become established by this time. IFN-gamma production by LNC was found to be further increased at the time of clinical manifestation of arthritis and could be up-regulated by co-culture with type II collagen. IL-10 was not detected in LNC cultures at the onset of arthritis and IL-4, although present, was found to be markedly suppressed in LNC cultures containing type II collagen. These findings indicate that Th1 responses are predominant at the time of onset of arthritis and that the activation of collagen-specific Th1 cells may result in suppression of Th2 activity. IFN-gamma production declined progressively during the progression and subsequent remission of arthritis whereas levels of IL-10 increased and low, though persistent, levels of IL-4 were detected throughout this period. High levels of IL-1 beta and TNF-alpha production were detected at the onset of the disease. The role of Th1 responses in the development of CIA was further emphasized by the observation that immunization of mice with type II collagen in incomplete Freund's adjuvant, which normally fails to induce arthritis, resulted in a predominantly Th2 cytokine profile.
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PMID:Relationship between Th1/Th2 cytokine patterns and the arthritogenic response in collagen-induced arthritis. 876 54

Intraarticular injection of zymosan (1 mg) into the knee joints of male Wistar rats led to infiltration of neutrophils and monocytes, joint swelling and elevation of tumour necrosis factor (TNF-alpha) in joint lavage fluids. Neutrophil infiltration was maximal at 5 h after induction of arthritis but had declined by 24 h post injection. Monocyte infiltration was maximal around the same time as that of the neutrophil infiltration but was sustained through 24 h. Joint swelling was apparent at 1 h but was not maximal until 6 h after induction of zymosan-induced arthritis. The maximum levels of TNF-alpha (150-200 pg of mouse equivalents per joint) in joint fluid preceded the infiltration of neutrophils and monocytes and was maximal at 1-2 h after injection of zymosan but had declined to below 100 pg per joint at 5 h (the time of maximal leukocyte infiltration) and was below the lower limit of detection at 24 h after induction of arthritis. Depletion of neutrophils and monocytes with a rabbit anti-rat leukocyte antibody reduced leukocyte infiltration and the later phase of joint swelling but did not reduce the levels of TNF-alpha in joint fluid. These data indicate that in zymosan-induced arthritis TNF-alpha is produced from the resident joint tissues such as the synovial lining cells rather than infiltrating neutrophils or monocytes.
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PMID:Resident joint tissues, rather than infiltrating neutrophils and monocytes, are the predominant sources of TNF-alpha in zymosan-induced arthritis. 877 70

Oxidative damage caused by oxygen free radicals from activated phagocytes contributes to the pathology of arthritis. The present study evaluates the activity of NADPH oxidase of neutrophils and monocytes from patients suffering from various inflammatory and autoimmune rheumatic disease. Production rates of reactive oxygen species [ROS] of neutrophils and monocytes from rheumatic patients are compared to those of healthy controls and non rheumatic disease controls and correlated with the plasma levels of tumor necrosis factor alpha, C-reactive protein and the sedimentation rates of erythrocytes. There was a two- to eightfold increase in phagocytic superoxide production in rheumatic patients, when compared to healthy subjects or patients with non-rheumatic internal diseases [p < 0.005]. The enhanced NADPH oxidase-dependent superoxide generation correlated well with elevated levels of tumor necrosis factor alpha [TNF-alpha] in plasma [p = 0.005], suggesting a causal relation. There was no correlation with the plasma levels of C-reactive protein and a weak though significant correlation with the sedimentation rates of erythrocytes [p = 0.043]. Removal of circulating TNF-alpha by dialysis of patients blood and inhibition of NADPH oxidase by prednisolone treatment normalized elevated ROS production to the levels of healthy controls and correlated with the clinical improvements. Our data support the hypothesis of a central role for TNF-alpha during the development of arthritis. The chemiluminescence assay described here may be useful as a convenient screen and as a potential follow up procedure for individual patients with rheumatic diseases.
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PMID:Priming of NADPH oxidase by tumor necrosis factor alpha in patients with inflammatory and autoimmune rheumatic diseases. 887 5

For a series of immunological diseases including asthma, inflammatory arthritis and experimental allergic encephalomyelitis the non-classical major histocompatibility complex (MHC) genetics of man and mouse has been making rapid progress. Information is available not only for the disease associations of individual candidate genes but also from the first genome scans. In both species the proinflammatory cytokine genes and/or their related receptors and inhibitors (IL-1, IL-1r, IL-1ra, IL-2, IL-6r, TNF-alpha), and to a lesser extent the anti-inflammatory cytokine IL-4 are implicated as candidate control elements. In contrast, genes for the signalling and adhesion CD molecules have so far been inconspicuous. Most of the polymorphisms so far detected have been in the regulatory sequences of these genes, rather than in the exons. It is suggested that the benefit conferred on an individual by greater flexibility in its immunoregulatory machinery may be responsible for maintaining this form of polymorphism.
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PMID:Non-classical-MHC genetics of immunological disease in man and mouse. The key role of pro-inflammatory cytokine genes. 889 33

The anti-inflammatory effects of the recently identified cytokine interleukin (IL)-13 on collagen-induced arthritis (CIA) was explored and compared to those of IL-4 using systemic administration of these cytokines via two injections of xenogeneic vector cells transfected with a plasmid construct. CIA was induced in DBA/I mice by immunization with native bovine type II collagen (CII). Chinese hamster ovary (CHO) fibroblasts transfected with the mouse IL-13 or IL-4 genes were inoculated subcutaneously on days 10 and 25 post-priming with CII and mice were monitored for signs of arthritis by observers unaware of the status of the animal. Incidence and severity of CIA were significantly reduced in the groups of mice treated with IL-13 and IL-4 gene-transfected CHO cells compared to control groups receiving nontransfected cells. Expression of various cytokines in spleen cells from individual mice was assessed by quantitative reverse transcriptase-polymerase chain reaction at different times after immunization. Our data show that IL-13-induced suppression of CIA coincided with a decreased TNF-alpha mRNA expression in the spleen of treated animals. This may explain at least partially the anti-inflammatory effects of IL-13 in CIA. Thus, our results may have important implications for the clinical use of T helper (Th)1/TH2 modulatory cytokines as therapeutic agents in the treatment of autoimmune diseases.
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PMID:Attenuation of collagen-induced arthritis in mice by treatment with vector cells engineered to secrete interleukin-13. 889 52

The cytokine network participates in the modulation of the immune system. Furthermore, the formation of the cytokine-receptor complex, as well as the transcription, translation, secretion, or degradation of cytokines interfere with the functions of cytokines. Cytokine inhibitors include antagonists, soluble receptors, cytokine-binding proteins, and cytokines that block other cytokines. In autoimmune diseases, an abnormal production of proinflammatory cytokines, or a reduced inhibition of their actions, may lead to an imbalance. The main cytokine inhibitors include interleukin-1 receptor antagonist (IL-1ra), soluble IL-1 receptor (sIL-1R), soluble TNF-alpha receptors (soluble TNF-Rs), and certain cytokines, such as IL-4, TGF beta, and IL-10. The combination of cytokine inhibitors is a potential therapeutic approach in the treatment of immunoinflammatory diseases. The nonspecific effects of immunosuppressive drugs are improved by using inhibitors with more specific actions on the functions of proinflammatory cytokines.
Semin Arthritis Rheum 1996 Oct
PMID:Cytokine inhibitors in autoimmune disease. 891 98

KE-298 is a new immunomodulatory agent with a chemical structure similar to that of D-penicillamine. We compared the effects of KE-298 on type II collagen-induced arthritis (CIA) in mice with those of prednisolone. KE-298 at a dose of 25 mg/kg showed only a decrease in the progression of foot pad swelling. At doses of 50 and 100 mg/kg, however, KE-298 inhibited the severity and development of the collagen-induced arthritis index, the progression of foot pad swelling, bone damage and histopathological changes. These inhibitory effects were more pronounced at the dose of 50 mg/kg than at 100 mg/kg. KE-298 also significantly inhibited the delayed-type hypersensitivity (DTH) response to type II collagen, but did not affect the production of anti-type II collagen IgG antibody in arthritic mice. To determine the inhibitory mechanism of KE-298, we studied the effect of KE-298 on IL-1 beta and TNF-alpha production in mice. We found that KE-298 inhibited bacterial lipopolysaccharide (LPS)-induced IL-1 beta production at doses of 50 and 100 mg/kg. It inhibited the production of TNF-alpha at the dose of 50 mg/kg, but not at 100 mg/kg. In summary, at appropriate dosages, KE-298 inhibited CIA and TNF-alpha production in mice. KE-298 also inhibited the DTH reaction to type II collagen and LPS-induced IL-1 beta production in a dose-related fashion. These findings suggest that these effects of KE-298 are closely related to its immunomodulatory action.
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PMID:Effect of KE-298 on experimental arthritis in mice. 893 Nov 4

Rheumatoid arthritis is characterized by a mononuclear infiltrate in the synovial tissue of the affected joints, considerable thickening of the synovial lining layer and concomitant destruction of cartilage and bone. Macrophages probably play a central role and the contribution of the synovial lining macrophages is addressed in studies in experimental murine arthritis models. Emphasis is given to the involvement in arthritis expression and cartilage destruction. The role of TNF-alpha and IL-1, and the modulatory cytokines IL-4/ IL-10 is briefly discussed.
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PMID:The role of macrophages in chronic arthritis. 893 61


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