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)

Therapeutic protocols for treating autoimmune diseases by feeding autoantigens during the disease process have not been very successful to date. In vitro it has been shown that beta-adrenergic agonists inhibit pro-inflammatory cytokine production and up-regulate anti-inflammatory cytokine production. We hypothesized that the protective effect of oral administration of Ag would be enhanced by oral coadministration of the beta(2)-adrenergic agonist salbutamol. Here we demonstrate that oral administration of salbutamol in combination with the Ag mycobacterial 65-kDa heat shock protein increased the efficacy of disease-suppressive tolerance induction in rat adjuvant arthritis. To study the mechanism of salbutamol in more detail, we also tested oral administration of salbutamol in an OVA tolerance model in BALB/c mice. Oral coadministration of OVA/salbutamol after immunization with OVA efficiently suppressed both cellular and humoral responses to OVA. Coadministration of salbutamol was associated with an immediate increase in IL-10, TGF-beta, and IL-1R antagonist in the intestine. The tolerizing effect of salbutamol/OVA was maintained for at least 12 wk. At this time point IFN-gamma production in Ag-stimulated splenocytes was increased in the OVA/salbutamol-treated animals. In conclusion, salbutamol can be of great clinical benefit for the treatment of autoimmune diseases by promoting oral tolerance induction.
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PMID:The beta 2-adrenergic agonist salbutamol potentiates oral induction of tolerance, suppressing adjuvant arthritis and antigen-specific immunity. 1239 Dec 18

Ligament injuries result in significant disability in over 100,000 patients each year. Despite current methods of treatment, 13% of patients with medial collateral ligament (MCL) injury develop early signs of arthritis, suggesting an incomplete return of knee stability. The principal hypothesis of this work was that the addition of TGF-beta 2 to the healing MCL would accelerate the development of scar strength and stiffness. Forty-four rabbits were divided evenly into four groups, with each group receiving either 0.1, 1 or 5 microg of TGF-beta 2 and the fourth group receiving 1 microg TGF-beta 2 and 1 microg of PDGF. Each rabbit underwent bilateral transection of the MCL, with one side having treatment with one of four doses of growth factor and the other side left untreated. All animals were sacrificed at 6 weeks and the structural properties of maximum load at failure, stiffness, and energy absorbed at failure measured. All treatment groups demonstrated an increase in scar mass, but no group had a significant increase in scar load at failure at 6 weeks. The addition of 0.1 microg TGF-beta 2 led to a significant increase in scar stiffness. The addition of PDGF had no significant effect on any of the parameters studied. This study suggests the mechanical stiffness, but not the load at failure, of ligament scar can be significantly altered by the administration of TGF-beta 2.
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PMID:The biomechanical response to doses of TGF-beta 2 in the healing rabbit medial collateral ligament. 1256 55

The objective of this study was to investigate the effect of the oral administration of type II collagen (CII) on pro-inflammatory mediator production by synoviocytes in rats with adjuvant arthritis (AA). Sprague-Dawley rats were fed with bovine CII either before immunization with Complete Freund's adjuvant (CFA) or after initiation of arthritis. Hind paw secondary swelling was measured and synoviocytes were harvested. Sera from portal vein of oral tolerized rats were collected and in vitro synoviocytes culture or synoviocytes-Peyer's Patches (PP) cells coculture system were developed. Interleukin (IL)-1 activity was measured by a mouse thymocyte activation assayed by MTT dye reduction and tumour necrosis factor (TNF) activity was measured by an L929 cytotoxicity bioassay. Nitric oxide (NO) and malondialdehyde (MDA) levels were measured by biochemical methods. We found that feeding with CII (5, 50 and 500 micro g/kg) for 7 days before immunization significantly suppressed hind paw secondary swelling measured at day 16, 20, 24 and 28 (all P < 0.01) and pro-inflammatory mediator (IL-1, TNF, NO and MDA) production by synoviocytes (all P < 0.01) in rats with AA. Feeding with CII (5, 50 and 500 micro g/kg) for 7 days after initiation of arthritis had a similar effect. CII (1, 10, 100 micro g/ml) had no effect on IL-1 and TNF production by synoviocytes in vitro, but CII 10 micro g/ml suppressed IL-1 and TNF production by synoviocytes-PP cells coculture system (P < 0.01), which was antagonized by anti-TGF-beta antibody (10 micro g/ml) (P < 0.01). Portal serum (1 : 10) from oral tolerized rats suppressed IL-1 and TNF production by synoviocytes (P < 0.01), which was also antagonized by anti-TGF-beta antibody (10 micro g/ml) (P < 0.01). We conclude that oral administration of CII had prophylactic and therapeutic effects on AA and over-production of IL-1, TNF, NO and MDA by synoviocytes was suppressed. Bystander active suppression may be the main mechanism of oral CII in the suppression of synoviocyte function.
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PMID:Oral administration of type II collagen suppresses pro-inflammatory mediator production by synoviocytes in rats with adjuvant arthritis. 1278 Jun 87

CD69 is induced after activation of leukocytes at inflammatory sites, but its physiological role during inflammation remains unknown. We explored the role of CD69 in autoimmune reactivity by analyzing a model of collagen-induced arthritis (CIA) in WT and CD69-deficient mice. CD69-/- mice showed higher incidence and severity of CIA, with exacerbated T and B cell immune responses to type II collagen. Levels of TGF-beta1 and TGF-beta2, which act as protective agents in CIA, were reduced in CD69-/- mice inflammatory foci, correlating with the increase in the proinflammatory cytokines IL-1beta and RANTES. Local injection of blocking anti-TGF-beta antibodies increased CIA severity and proinflammatory cytokine mRNA levels in CD69+/+ but not in CD69-/- mice. Moreover, in vitro engagement of CD69 induced total and active TGF-beta1 production in Concanavalin A-activated splenocyte subsets, mouse and human synovial leukocytes, and Jurkat stable transfectants of human CD69 but not in the parental CD69 negative cell line. Our results show that CD69 is a negative modulator of autoimmune reactivity and inflammation through the synthesis of TGF-beta, a cytokine that in turn downregulates the production of various proinflammatory mediators.
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PMID:CD69 downregulates autoimmune reactivity through active transforming growth factor-beta production in collagen-induced arthritis. 1297 72

Oral tolerance (OT) consists of the oral administration of antigens (Ag) that could alter the response of the immune system. This is a form of peripheral immune tolerance in which mature lymphocytes in the peripheral lymphoid tissues are rendered non functional or hyporesponsive by prior oral administration of Ag. It was first described in 1911 in animal models of anaphylaxis. This therapeutic approach requires the orally administration of Ag and the active participation of the gut-associated lymphoid tissue (GALT), a tissue comprising Peyer's patches, intraepitelial cells and villi containing epithelials cells which is a well organized immune network. The mechanisms by which OT is mediated included deletion or anergy and active cellular suppression. The primary factor determining which form of tolerance will be developed after oral administration of Ag is the Ag dosage. Thus, it is thought that low doses of Ag induce the generation of active suppression, via regulatory T cells in the GALT, which then migrate to the systemic immune system. These regulatory T cells produce down-regulatory cytokines such as IL4, IL10 and TGFbeta, a Th2 / Th3 cytokine pattern. Conversely, high dose of Ag favors anergy or clonal deletion. The phenomenon in which regulatory cells, as generated by oral tolerization, are primed in an Ag specific manner, but act in the respective microenvironment in a non-Ag specific manner is called bystander suppression. This phenomenon is of particular interest and explained the use of OT in T cell mediated autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS) and type I diabetes, some diseases in which the autoAg remains unknown or where there are reactivities to multiple autoAgs. There were several studies demonstrating the effectiveness of orally administered Ag in different animal models of autoimmune diseases, such as experimental allergic encephalomyelitis, collagen induced arthritis, diabetes, but also uveitis, myastenia gravis and transplantation. These mouse or rat models of autoimmune diseases gave the rationale for the therapeutic use of OT in human and this therapeutic approach has been tried in MS and RA, using oral myelin or oral collagen, respectively. In RA, 4 trials of oral type II collagen (CII) in RA have been published. Taken together, these studies suggested that oral CII in RA gave a trend toward clinical improvement, with significance in only 2 studies. Bacterial extract from Escherichia coli containing heat shock proteins has been tried in oral treatment for RA. Two placebo controlled trials and 2 comparative studies gave favorable results for this bacterial extract with no or mild adverse events. Although oral/mucosal tolerance has given successful results in animal models of autoimmune diseases, the enthusiasm for this therapeutic approach in human diseases must be tempered. The discrepancies between the effectiveness of OT in animal models and the results in human trials raise some questions, the identification of the subgroup of patients who might respond to this treatment and the source (or nature) of the administered Ag (homologous versus heterologous), for instance.
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PMID:Oral tolerance in the treatment of rheumatoid arthritis. 1456 Dec 5

MRL/Mp mice bearing the Fas deletion mutant gene, lpr (MRL/lpr), spontaneously develop polyarthritis, sialoadenitis and dacryoadenitis, resembling rheumatoid arthritis (RA), and also corneal involvement such as keratopathy and scleritis, which is a major complication in RA patients. In this study, we found that the expression levels of IL-1beta and MMP-1 mRNAs in cornea were high in both MRL/lpr and MRL/Mp-+/+ strains of mice at an age younger than when they develop any inflammatory lesions. This was not true of other inbred strains, even those bearing the lpr gene, and also not of (NZB x NZW) F1 lupus mice. There was no significant difference in the expression of IL-1alpha and TGFbeta in cornea in these strains. Using crosses between MRL/lpr and C3H/HeJ-lpr/lpr (C3H/lpr) mice, at least the expression of IL-1beta was found to be under the control of the MRL genetic background, likely with a recessive mode of inheritance. Considering that IL-1beta in cornea was detected particularly in the epithelial layer, the high expression of IL-1beta in cornea is most likely involved in the genetic predisposition for corneal involvement and possibly also for arthritis in an MRL strain of mice.
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PMID:High expression of interleukin-1beta in the corneal epithelium of MRL/lpr mice is under the control of their genetic background. 1508 86

The aim of the study was to characterise the profile and clinical correlates (arthritis, rash, and fatigue) of cytokines, chemokines, and other mediators in symptomatic acute parvovirus B19 infection. Serum was examined from cases of acute B19 infection (as defined by serum anti-B19 IgM positivity) (n = 84), and in normal persons (n = 43) for B19 markers (serum B19 antibodies and DNA), rheumatoid factor (RF), and antinuclear antibody (ANA). A panel of cytokines/chemokines was measured in duplicate using the Bioplex Protein Array system (BioRad Hemel Hempstead, UK). These included interleukin-1 beta (IL-1 beta), IL-4, IL-5, IL-6, IL-8, IL-13, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), macrophage chemoattractant protein-1 (MCP-1), granulocyte-monocyte colony stimulating factor (GM-CSF), transforming growth factor-beta1 (TGF-beta 1), endothelin-1 (ET-1), and neopterin. Acute symptomatic infection was characterised by specific IgG positivity (83%), serum B19 DNA positivity (96%), and raised levels of IL-4, IL-6, IL-8, TNF-alpha, IFN-gamma, MCP-1, GM-CSF, TGF-beta 1, and ET-1. Patients with acute B19-associated arthritis were found to have lower levels of IL-6, TNF-alpha, and GM-CSF than patients without arthritis, while those with rash had lower levels of TGF-beta 1. It is concluded that cytokine levels following acute symptomatic infection with parvovirus B19 indicate a state of immune activation. The profile of circulating mediators may provide insights into the possible pathogenesis of particular clinical manifestations of this infection.
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PMID:Circulating cytokines and chemokines in acute symptomatic parvovirus B19 infection: negative association between levels of pro-inflammatory cytokines and development of B19-associated arthritis. 1525 81

A relative high secretion level of IL-10 and a low secretion of TNF-alpha has been described in the synovial fluid and peripheral blood of patients with reactive arthritis (ReA), possibly contributing to the persistence of bacteria. The role of TGF-beta is less clear. We investigated these cytokines in the synovial membrane of patients with ReA and rheumatoid arthritis (RA) and tried to identify their cellular source. We used sections from the synovial membrane of 4 ReA and 4 RA patients which were double stained with immunofluorescence antibodies against cell surface markers for T cells (CD3), macrophages (CD68) and B cells (CD20) in combination with antibodies against intracellular cytokines TNF-alpha, IFN-gamma, TGF-beta, IL-4 and IL-10, and quantified these using a fluorescence microscope. A lower number of TNF-alpha-secreting cells were found in ReA compared to RA: CD3+: 1.78 +/- 0.54% versus 5.02% +/- 0.47% (p = 0.034). CD68+: 2.86 +/- 0.52 versus 5.37 +/- 0.53% (p = 0.034), CD20+ : 3.02 +/- 0.42% versus 3.58 +/- 0.48% (p > 0.05). A higher number of IL-10 positive cells were found in ReA compared to RA: CD3+: 3.27 +/- 1.5% versus 1.13 +/- 0.50% (p = 0.034), CD68+ 1.23 +/- 0.75% versus 0.83 +/- 0.35% (p > 0.05), CD20+: 3.70 +/- 1.6% versus 1.6 +/- 1.1% (p > 0.05). A difference between ReA and RA was also found for TGF-beta+ T cells: CD3+ 7.86 + 1.5% versus 1.78 + 0.35% (p = 0.032); CD20+: 7.91 + 2.1% versus 2.1 + 2.8% (p > 0.05), CD68+: 7.81% + 1.24% versus 2.12 + 0.28% (p = 0.032). In conclusion, we saw a different cytokine secretion pattern in the synovial membrane of ReA and RA. For T cells in ReA we found a cytokine secretion profile typical for T regulatory cells 1 (Tr1), with an elevated level of IL-10- and TGF-beta-secreting cells. Whether this is due to a more general difference in TNF-alpha, IL-10 or TGF-beta production which is genetically determined or regulated by T cells remains to be determined.
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PMID:An elevated level of IL-10- and TGFbeta-secreting T cells, B cells and macrophages in the synovial membrane of patients with reactive arthritis compared to rheumatoid arthritis. 1545 15

Transforming growth factor (TGF-beta1) is a potent inducer of chondrogenesis and stimulant of cartilage extracellular matrix (ECM) synthesis. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is located in ECM and is the major inhibitor of matrix metalloproteinases (MMPs) and aggrecanase, the principal enzymes implicated in collagen and aggrecan degradation in arthritis. We investigated the role of extracellular-signal-regulated kinase (ERK)-mitogen-activated protein kinases (MAPK) and Sp1 transcription factor in TGF-beta-induced TIMP-3 gene in chondrocytes and chondrosarcoma cells. TGF-beta time-dependently induced a sustained phosphorylation of ERK-MAPKs in primary human or bovine chondrocytes. Inhibitors of this pathway, PD98059 and U0126, downregulated TGF-beta-induced expression of TIMP-3 RNA and protein. Since the ERKs can phosphorylate Sp1, and the promoter of human TIMP-3 gene contains four Sp1-binding sites, we investigated whether Sp1 is a downstream target of this pathway. Mithramycin and WP631, the agents that prevent binding of Sp1 to its consensus site, downregulated TGF-beta-inducible TIMP-3 expression. Indeed, mithramycin blocked TGF-beta-stimulated Sp1 binding activity. Transfection of cytomegalovirus (CMV) promoter-Sp1 plasmid increased TIMP-3 promoter (-940 to +376)-driven luciferase activity. Depletion of Sp1 by transfection of an antisense phosphorothioate oligonucleotide suppressed TGF-beta-induced TIMP-3 protein expression, while its sense homolog had no effect. These results suggest that activation of ERK-MAPK pathway and Sp1 transcription factor play a pivotal role in the induction of TIMP-3 by TGF-beta in chondrocytes.
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PMID:TGF-beta-induced expression of tissue inhibitor of metalloproteinases-3 gene in chondrocytes is mediated by extracellular signal-regulated kinase pathway and Sp1 transcription factor. 1546 69

Osteoarthritis is the most common form of human arthritis. We investigated the potential role of asporin, an extracellular matrix component expressed abundantly in the articular cartilage of individuals with osteoarthritis, in the pathogenesis of osteoarthritis. Here we report a significant association between a polymorphism in the aspartic acid (D) repeat of the gene encoding asporin (ASPN) and osteoarthritis. In two independent populations of individuals with knee osteoarthritis, the D14 allele of ASPN is over-represented relative to the common D13 allele, and its frequency increases with disease severity. The D14 allele is also over-represented in individuals with hip osteoarthritis. Asporin suppresses TGF-beta-mediated expression of the genes aggrecan (AGC1) and type II collagen (COL2A1) and reduced proteoglycan accumulation in an in vitro model of chondrogenesis. The effect on TGF-beta activity is allele-specific, with the D14 allele resulting in greater inhibition than other alleles. In vitro binding assays showed a direct interaction between asporin and TGF-beta. Taken together, these findings provide another functional link between extracellular matrix proteins, TGF-beta activity and disease, suggesting new therapeutic strategies for osteoarthritis.
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PMID:An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. 1564 Aug


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