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)

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

In the present study we investigated the effect of a potent anti-inflammatory cytokine, interleukin (IL)-10, on the development of collagen-induced arthritis (CIA) in mice. Each DBA1/J mouse was immunized with 200 micrograms of native collagen and followed by booster injections at 3 weeks. rmIL-10 was injected i.p. daily at a dose of 100 ng/mouse. Mice were divided into four groups according to the administration period of rmIL-10. As a result, a 48-day course of IL-10 treatment significantly suppressed the severity of arthritis. Among the 4 groups, the most pronounced suppression was observed in the group in which IL-10 was given from day 0 to 21. On the other hand, there were no significant differences in the serum IgG anti-type II collagen (CII) titers between the four groups. Moreover, the production of cytokines (IL-6 and tumor necrosis factor-alpha (TNF-alpha)) and other mediators (prostaglandin E2 (PGE2) and nitric oxide (NO)) by peritoneal macrophages seemed to show no clear correlation with the severity of arthritis in mice. These results raise the possibility that IL-10 might be a useful agent for suppressing the progression and the development of CIA in mice.
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PMID:Effect of IL-10 on collagen-induced arthritis in mice. 881 59

Immunization of DBA/1 mice with bovine type II collagen (CII) in complete Freund's adjuvant (CFA) leads to collagen-induced arthritis as evidenced by joint inflammation. In this study, reverse transcription-polymerase chain reaction (RT-PCR) was used to demonstrate the activation of genes encoding for IL-2, IFN-gamma, and IL-10 in the lymph nodes from both CII-immunized and control CFA-immunized DBA/1 mice, at Days 10, 40, and 70 after immunization, in the absence of any IL-5 or IL-13 transcription. By quantitative RT-PCR, the levels of IFN-gamma mRNA in response to CII could not be quantitatively differentiated from the IFN-gamma transcribed in response to CFA alone. In the joints of CII-immunized mice, IL-1beta and IL-10 mRNA were found in the absence of IL-5 or IFN-gamma. Synovial IL-1beta and IL-10 were expressed most strongly at the time of clinical symptoms, 40 days after immunization. Together, these findings suggest that immunization with CII in CFA induces a type 1 response against the adjuvant, giving a cytokine environment which influences the T cells responding to CII to become type 1 T cells. This is manifested here by the appearance of gene activation in synovial tissue of collagen-immunized mice, but not in adjuvant-immunized control animals.
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PMID:Collagen-induced arthritis in DBA/1 mice: cytokine gene activation following immunization with type II collagen. 891 86

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

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

Recent studies have demonstrated that the treatment of mice with anti-gp39 antibodies impairs T-cell functions in the murine collagen type II-induced arthritis model, in acute semi-allogenic graft-versus-host disease, and in the allo-specific CTL-reaction, that is, reactions that are believed to be mediated by Th1-type T cells. On the other hand, the administration of anti-gp39 antibody did not influence Th2 T-cells responses, suggesting that CD40-CD40L interactions are more crucial for Th1 than Th2 T-cell development. Recent studies also demonstrate that dendritic cells (DC) are capable of driving a Th1 T-cell response that is mediated by IL-12. In addition, stimulation of CD40 on human monocytes results in IL-12 production, suggesting that activated T cells expressing CD40L may directly induce the production of IL-12 by antigen-presenting cells, thus allowing for the generation of a Th1 T-cell response in the absence of intracellular pathogens. We investigated whether the CD40-CD40L interaction was important in the production of IL-12 by DCs in an in vitro system that allowed precise control of cytokine concentrations. Initially we showed that FACS-purified mouse spleen DCs produce high amounts of IL-12 p40 in response to CD40 crosslinking by CD40L-expressing fibroblasts. We then demonstrate that DCs also produce IL-12 p40 in a more physiologic system using purified DCs pulsed with ovalbumin (OVA) and then cultured with LECAM-1hi T cells from ovalbumin T-cell receptor transgenic mice. Finally, we show that IL-10 has a potent capacity to shut down CD40-induced IL-12 p40 secretion; and, in addition, IL-4 partially inhibits CD40-induced IL-12 p40 secretion and enhances IL-10-mediated inhibition in an additive fashion. We also investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (TNBS)-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response completely prevented IFN-gamma production by CD4 T cells from the intestinal lamina propria and also the clinical and histological evidence of disease. In further studies we showed that the prevention of disease activity was due to an inhibition of IL-12 secretion. Thus, the injection of recombinant IL12 p75 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. In conclusion, these findings suggest that DCs produce IL-12 in response to CD40 signaling, that a mechanism by which IL-4 may induce Th2 development is by acting with IL-10 to inhibit IL-12 production by DCs, and that the CD40L-CD40 interaction is crucial for the IL-12-dependent priming of Th1 T cells in vivo.
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PMID:Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T-cell responses. 895 22

The collagen-induced arthritis model in DA rats induced with homologous rat type II collagen was chosen to determine the therapeutic capacity and effects on autoimmunity by IL-10. Systemic IL-10 treatment (100 or 10 micrograms/day) with mini-osmotic pumps during the periods of arthritis onset (days 12-20 after immunization) decreased the frequency of arthritis and delayed the onset and reduced the severity of arthritis in the few rats that eventually developed arthritis. Concomitantly, levels of autoantibodies to CII were reduced. To test the activity on established arthritis, IL-10 was administered subcutaneously in the paws. This treatment reduced the swelling but did not block the arthritis process. The effective treatment required 100 micrograms of IL-10 every 12th hour while 50 micrograms of IL-10 had little effect, although a tendency of reduced paw swelling was observed. Surprisingly, therapeutic IL-10 treatment led to higher serum levels of autoantibodies to CII. The highest doses of IL-10 (100 micrograms) did not show any apparent toxic effects when given locally or systematically. Taken together, this study suggests that IL-10 is a candidate for treatment of rheumatoid arthritis.
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PMID:Interleukin-10 suppresses the development of collagen type II-induced arthritis and ameliorates sustained arthritis in rats. 897 43

DBA/1 mice were administered type II collagen (CII) or collagen peptides intranasally before systemic immunization to determine whether tolerance could be induced and autoimmune arthritis suppressed. Although prior experiments have demonstrated that collagen given intravenously or orally is effective, the respiratory mucosal route offers several theoretical advantages for dosing peptides, in addition to ease of use. Intact CII, CB11 and a synthetic peptide containing the immunodominant T-cell epitope recognized by H-2q mice were all effective in reducing the incidence and severity of arthritis and the immune response to CII. Since previous studies have demonstrated the importance of IgG2 antibody subclasses to the induction of collagen-induced arthritis, total immunoglobulin G (IgG), IgG1, and IgG2a and IgG2b were measured. IgG2 antibody subclasses were significantly downregulated by the treatment regimen, whereas a slight decrease in IgG1 antibodies was noted that was not significant. In an effort to determine the mechanism by which arthritis was attenuated, cervical lymph node and spleen cells from treated mice were cultured separately with CII and supernatants tested for the presence of T-cell lymphokines. The cells provided a T-helper 2 (Th2)-like response to CII, with T cells from lymph nodes secreting interleukin-4 (IL-4) and splenocytes secreting both IL-4 and IL-10, whereas a Th1-like response was detected in immunized mice not tolerized with CII. These findings indicate that the downregulation of arthritis that occurs with intranasal administration of CII is associated with Th2-type lymphokine profile and a decrease in complement-fixing antibody subclass.
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PMID:Suppression of murine collagen-induced arthritis by nasal administration of collagen. 913 41

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.
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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


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