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)

Various lines of evidence suggest a close relationship between heat shock proteins (hsp) and several autoimmune diseases such as arthritis, diabetes and multiple sclerosis. While enhanced expression of hsp in autoimmune diseases is often regarded as a non-specific bystander effect of the inflammatory process, surprisingly little is known on hsp regulation by inflammatory mediators such as cytokines. In this study cytokine-induced expression of hsp60, hsp27 and alphaB-crystallin was studied in cultures of primary human adult astrocytes at the mRNA as well as at the protein level. We show differential hsp expression patterns in response to pro-inflammatory and immunoregulatory cytokines. Hsp60 expression was found to be enhanced in response to cytokines as diverse as IL-1beta, TNF-alpha, IL-4, IL-6 and IL-10. Upregulation of hsp27, however, was primarily induced by immunoregulatory cytokines like IL-4, IL-6 and TGF-beta whereas alphaB-crystallin expression was found to be enhanced by the pro-inflammatory cytokine TNF-alpha only. None of the cytokines studied was able to enhance expression of all three hsp simultaneously. These results show that in human astrocytes induced expression of hsp27 and alphaB-crystallin is dependent on the presence of a defined set of stimuli, while induced expression of hsp60 is a much less selective event. This highly differential pattern of hsp expression in response to inflammatory mediators known to play an important role in the pathogenesis of autoimmune diseases indicates that hsp responses are specific rather than non-specific bystander responses.
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PMID:Differential expression of stress proteins in human adult astrocytes in response to cytokines. 1081 78

Members of the matrix metalloproteinase family of enzymes degrade specific components of the extracellular matrix. MMP-9 is a type IV/V collagenase necessary for normal osteogenesis and is increased in inflammatory and neoplastic conditions. In such destructive diseases as emphysema and arthritis, and in epithelial cancers, MMP-9 is produced by cells of the monocyte lineage. Fetuin, a prominent serum glycoprotein, binds to and inactivates TGF-beta family members and through this mechanism regulates osteogenesis (Binkert et al., 1999, J Biol Chem 274:28514-28520.). We studied the effects of TGF-beta1 and fetuin on proMMP-9 release by the human monocyte line THP-1. Exogenous TGF-beta1 stimulated proMMP-9 release by THP-1 cells, with half-maximal stimulation at approximately 0.01 ng/ml TGF-beta1. Human fetuin (0.5-2 microM) partially inhibited this stimulation. Human fetuin alone stimulated THP-1 monocyte proMMP-9 release, with half maximal stimulation at approximately 0.25 microM fetuin. Neutralizing antibody specific for TGF-beta1 also stimulated proMMP-9 release, suggesting that endogenously-derived TGF-beta1 has an inhibitory effect. In freshly isolated human peripheral blood monocytes, fetuin stimulated proMMP-9 release with a dose-response curve similar to that observed in THP-1 cells. Human fetuin also activated proMMP-9 present in THP-1 conditioned medium. Taken together, these data suggest that under physiological conditions, fetuin facilitates matrix degradation by monocyte-derived MMP-9, both by opposing the autocrine inhibitory effect of endogenous TGF-beta1 on proMMP-9 release, and by activating proMMP-9 in the pericellular milieu. Conversely, fetuin may limit the stimulation of monocyte proMMP-9 release by high levels of exogenous TGF-beta1. Such modulation could prove important under pathological conditions where TGF-beta1 derived from paracrine sources is abundant, such as in epithelial malignancies.
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PMID:Regulation of human monocyte proMMP-9 production by fetuin, an endogenous TGF-beta antagonist. 1102 39

Because the gastrointestinal mucosa is a vast interface between the body and the environment, it is the main entry site for many environmental antigens. Enterocytes can cleave environmental antigens into peptides, bind these peptides to their CD1 receptor, and present them to T cells. Intact antigens can penetrate through specialized Peyer's patch enterocytes called 'M cells'; they are then degraded and presented by dendritic cells to Peyer's patch T cells. The influx of multiple antigens through the gastrointestinal mucosa usually results in tolerance. High-dose tolerance is due to T cell deletion or anergy, whereas low-dose tolerance involves activation of TGFbeta-producing Th2 or Th3 cells. TGFbeta inhibits lymphocyte proliferation and the production of antibodies to ingested antigens; in addition, it blocks the proliferation of lymphocytes in organs to which gastrointestinal Th3 lymphocytes migrate. This 'innocent bystander' effect has been used to try to induce oral tolerance. For instance, pretreatment with oral bovine type II collagen has proved capable of modulating several models of experimental polyarthritis. Arthritis severity was considerably reduced. Preliminary attempts in humans with rheumatoid arthritis have yielded promising results.
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PMID:Oral immunomodulation therapy in rheumatoid arthritis. 1114 4

This study was performed to elucidate pathophysiological events before and during the course of collagen-induced arthritis in Dark Agouti rats, a model for rheumatoid arthritis. Kinetic studies of local cytokine responses were determined using immunohistochemical techniques, quantified by computer-assisted image analysis. We recently reported that the macrophage-pacifying agent CNI-1493 successfully ameliorated collagen-induced arthritis. In the present trial, we investigated the potential of CNI-1493 to down-regulate pro-inflammatory cytokines. Synovial cryosections were analyzed at various time points for the presence of interleukin (IL)-1beta, tumor necrosis factor (TNF), and transforming growth factor (TGF)-beta. Unexpectedly, an early simultaneous TNF and IL-1beta expression was detected in resident cells in the lining layer, preceding disease onset and inflammatory cell infiltration by >1 week. The predominant cytokine synthesis by synovial (ED1+) macrophages coincided with clinical disease. TNF production greatly exceeded that of IL-1beta. CNI-1493 treatment did not affect the early disease-preceding TNF and IL-1beta synthesis in the lining layer. However, after disease onset, CNI-1493 intervention resulted in a pronounced reduced IL-1beta and in particular TNF expression. Furthermore, CNI-1493 significantly up-regulated synthesis of the anti-inflammatory cytokine TGF-beta and thereby shifted the balance of pro-inflammatory and anti-inflammatory cytokines in the arthritic joint in a beneficial way.
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PMID:Dynamics of early synovial cytokine expression in rodent collagen-induced arthritis : a therapeutic study using a macrophage-deactivating compound. 1115 86

The aim of this study was to understand the immune processes controlling the initiation and spontaneous resolution of adjuvant arthritis (AA). We investigated synovial T-cell recruitment and mRNA expression of IL-17 and other important disease related cytokines, IFN-gamma, IL-2, IL-4, TNF and TGF-beta in inguinal lymph node (ILN) and synovial membrane (SM). Arthritis severity was assessed by a numerical rating score and rats were sacrificed every 3--4 days postadjuvant induction. Further assessment involved quantitative radiology and histology of the ankle joints on each day, and the ILN and SM were removed for RNA extraction. Cytokine mRNA expression was measured using RT-PCR and densitometry. Paraffin sections of rat ankle joints were stained for T-cells (CD3) by immunohistochemistry. In the ILN, there was an increase in IL-17, TNF and IFN-gamma expression in the early stages of disease, with a secondary sustained increase in IFN-gamma expression. In the SM, there was expression of T-cell cytokines in early arthritis (day 13), and prolonged TNF and TGF-beta expression, which reflected disease progression. IL-4 mRNA expression increased in the later stages of AA. Synovial T-cell numbers transiently increased at day 6, and remained high from days 13--28. Increased pro-inflammatory cytokine expression, including IL-17, in the ILN reflects the initiating events in the early stage of disease. IL-17 may therefore play an important role in the pathogenesis of AA. The increase in IL-4 (an anti-inflammatory cytokine) in the SM in the later stages of AA suggests that IL-4 is involved in the spontaneous resolution of AA. The initial increase in IFN-gamma in the ILN may reflect a pro-inflammatory response, while the prolonged secondary increase may indicate activation of regulatory T-cells.
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PMID:Cytokine expression and synovial pathology in the initiation and spontaneous resolution phases of adjuvant arthritis: interleukin-17 expression is upregulated in early disease. 1129 38

The extracellular matrix of articular cartilage consists mainly of type II collagen and large aggregating proteoglycan (aggrecan). During arthritis and other joint diseases, the proteoglycan (PG) level of cartilage matrix is diminished, leading to impairment of normal joint function. A new method is described for measuring the changes in PG content of murine articular cartilage. The method is based on the automated densitometric analysis of patellar cartilage of standard, safranin O-stained sections of whole murine knee joints. It appeared to be possible to measure optical density in parallel layers of articular cartilage with high reproducibility. Approximately 25 sections can be evaluated within 1 h. Measuring a single section 10 times resulted in a coefficient of variation (CV) of 0.1-1.4%. A mean CV of 5-14% was calculated when a group of 18 sections was analyzed in quintuplicate. To validate the procedure, changes in PG content induced by arthritis or by intra-articular injection of TGFbeta-1 were analyzed by the image analysis method, the dimethylmethylene blue (DMB) assay and by visual grading. Although not a quantitive method, the newly developed image analysis method appeared to be more sensitive in detecting significant change in PG content of murine articular cartilage than the DMB method or visual grading. The image analysis method makes it possible to measure changes in PG content of specific areas of articular cartilage with higher sensitivity than the DMB method and eliminating the bias inherent to visual grading by human observers.
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PMID:Analysis of changes in proteoglycan content in murine articular cartilage using image analysis. 1155 Jun 80

Viral and nonviral gene therapy vectors have been successfully employed to deliver inflammatory cytokine inhibitors (anticytokines), or anti-inflammatory cytokines, such as transforming growth factor beta-1 (TGF-beta 1), which protect against experimental autoimmune diseases. These vectors carry the relevant genes into a variety of tissues, for either localised or systemic release of the encoded protein. Administration of cDNA encoding soluble IFN-gamma receptor (IFN-gamma R)/IgG-Fc fusion proteins, soluble TNF-alpha receptors, or IL-1 receptor antagonist (IL-1ra), protects against either lupus, various forms of arthritis, autoimmune diabetes, or other autoimmune diseases. These inhibitors, unlike many cytokines, have little or no toxic potential. Similarly, TGF-beta 1 gene therapy protects against numerous forms of autoimmunity, though its administration entails more risk than anticytokine therapy. We have relied on the injection of naked plasmid DNA into skeletal muscle, with or without enhancement of gene transfer by in vivo electroporation. Expression plasmids offer interesting advantages over viral vectors, since they are simple to produce, non-immunogenic and nonpathogenic. They can be repeatedly administered and after each treatment the encoded proteins are produced for relatively long periods, ranging from weeks to months. Moreover, soluble receptors which block cytokine action, encoded by gene therapy vectors, can be constructed from non-immunogenic self elements that are unlikely to be neutralised by the host immune response (unlike monoclonal antibodies [mAbs]), allowing long-term gene therapy of chronic inflammatory disorders.
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PMID:Anticytokine gene therapy of autoimmune diseases. 1172 11

Oral tolerance to myelin basic protein (MBP) is an effective antigen-specific method to suppress experimental allergic encephalomyelitis (EAE). Glatiramer acetate [copolymer 1 (Cop1)] is a synthetic copolymer designed to mimic MBP which suppresses EAE, is used parenterally to treat multiple sclerosis (MS) and is being tested orally for efficacy in MS. We investigated the immunologic properties of Cop1 to determine the degree to which its effects were antigen specific using MBP TCR transgenic mice. Immunization of MBP TCR transgenic mice fed Cop1, MBP or MBP Ac1-11 resulted in decreased proliferation, and IL-2, IL-6 and IFN-gamma production, and increased secretion of IL-10 and transforming growth factor (TGF)-beta in Cop1-fed animals. IFN-gamma was decreased, and IL-10 and TGF-beta were increased in non-immunized mice fed Cop1 and stimulated in vitro with MBP. No such effects were observed in ovalbumin TCR transgenic mice. To determine if the effects of Cop1 were specific to MBP TCR-bearing cells, MBP TCR transgenic Rag2(-/-) mice were immunized and re-stimulated in vitro with Cop1. We found a marked increase in IL-4 and similar increases in IL-4 after feeding Cop1. In disease models, feeding Cop1 suppressed EAE in MBP TCR transgenic mice, (PL/J x SJL)F(1) mice, and in myelin oligodendrocyte glycoprotein-induced EAE in NOD mice. Oral Cop1 had no effect on collagen-induced arthritis. These results demonstrate that Cop1 is active orally in an antigen-specific fashion, and may function as an altered peptide ligand for MBP-specific TCR-bearing cells by decreasing pro-inflammatory cytokines (IFN-gamma) and increasing anti-inflammatory cytokines (IL-4, IL-10 and TGF-beta).
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PMID:Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines. 1180 32

Regulatory T cells prevent autoimmunity by suppressing the reactivity of potentially aggressive self-reactive T cells. Contact-dependent CD4+ CD25+ 'professional' suppressor cells and other cytokine-producing CD4+ and CD8+ T-cell subsets mediate this protective function. Evidence will be reviewed that T cells primed with transforming growth factor (TGF)-beta expand rapidly following restimulation. Certain CD4+ T cells become contact-dependent suppressor cells and other CD4+ and CD8+ cells become cytokine-producing regulatory cells. This effect is dependent upon a sufficient amount of IL-2 in the microenvironment to overcome the suppressive effects of TGF-beta. The adoptive transfer of these suppressor cells generated ex vivo can protect mice from developing chronic graft-versus-host disease with a lupus-like syndrome and alter the course of established disease. These data suggest that autologous T cells primed and expanded with TGF-beta have the potential to be used as a therapy for patients with systemic lupus erythematosus and other chronic inflammatory diseases. This novel adoptive immunotherapy also has the potential to prevent the rejection of allogeneic transplants.
Arthritis Res 2002
PMID:The potential of human regulatory T cells generated ex vivo as a treatment for lupus and other chronic inflammatory diseases. 1210 94

Metallothionein is a low molecular weight, cysteine-rich, stress response protein that can act as an antioxidant and as an immunosuppressive agent in instances of antigen-dependent adaptive immunity. In this context, we assessed the therapeutic potential and mechanisms of action of metallothionein in a collagen-induced arthritis model. Repeated administration of metallothionein-I + II during the course of disease dramatically reduced the incidence and severity of the disease. Joint tissues isolated from boostered paws of metallothionein-I + II-treated mice expressed significantly reduced levels of proinflammatory mediators, such as tumour necrosis factor (TNF)-alpha and cyclooxygenase-2, when compared with those of control-treated mice. Lymph node cells obtained from metallothionein-I + II -injected mice exhibited a significant decrease in the proliferative response and a remarkable increase in tumour growth factor (TGF)-beta production in response to type II collagen. Taken together, these results suggest that metallothionein-I + II promote the development of type II collagen-specific, TGF-beta-producing cells to antagonize the expansion of arthritogenic cells. This could lead to local suppression of inflammatory responses by inhibiting the expression of proinflammatory molecules. Thus, this study demonstrates the suppressive effects of metallothionein on collagen-induced arthritis, and indicates that there may be a potential therapeutic application for manipulation of metallothionein during the treatment of autoimmune disorders.
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PMID:Metallothionein suppresses collagen-induced arthritis via induction of TGF-beta and down-regulation of proinflammatory mediators. 1216 78


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