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)

The aim of this study was to investigate the effects of IL-1 beta and TNF-alpha on NGF levels in the knee joint in experimentally induced arthritis in adult mice. Out data showed that IL-1 beta, but not TNF-alpha, induces an increase in NGF levels, while concomitant injection of both cytokines enhances the effect of IL-1 beta on NGF presence. Analysis of NGF levels in the knee joint of carrageenan- and IL-1 beta-induced inflammation after administration of antibodies against TNF-alpha supports this hypothesis. Our studies also showed that exogenous administration of NGF antibody reduces the enhanced level of TNF-alpha occurring in arthritic mice. This latter observation indirectly suggests that NGF is implicated in the upregulation of TNF-alpha in these animal models of joint inflammation. The functional significance of NGF or NGF antibody in inflammatory arthritis is discussed.
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PMID:Role of IL-1 beta and TNF-alpha in the regulation of NGF in experimentally induced arthritis in mice. 983 49

Oral administration of autoantigens can influence the outcome of experimental autoimmune diseases, yet little is known about nonself Ag-induced tolerance. In this study, we administered group A streptococcal cell wall (SCW) peptidoglycan-polysaccharide complexes orally and monitored the impact on SCW-induced erosive polyarthritis. Oral administration of low dose SCW (3 microg/day), initiated 7 days before an arthritogenic dose of systemic SCW, virtually eliminated the joint swelling and destruction typically observed during both the acute and chronic phases of the arthritis. High (300 microg), but not intermediate (30 microg), dose regimens also profoundly inhibited the disease. Most previous studies have demonstrated that prior feeding is required for efficacy, yet oral feeding of low dose SCW suppressed the evolution of arthritis even when administration was begun 10-15 days after induction of the arthritis. While the synovial inflammatory cell infiltration and expression of proinflammatory cytokines were markedly suppressed, no local enhancement of the regulatory cytokines IL-4, IL-10, and TGF-beta was detected. Oral administration of low dose SCW, however, up-regulated circulating levels of TGF-beta, concomitant with decreased circulating TNF-alpha and suppression of chronic arthritis. Moreover, IL-10 was increased in tolerized spleen lymphocytes, and unexpectedly, this SCW-specific IL-10 production was TGF-beta dependent. These data support a pivotal role for TGF-beta, although not necessarily in the joint, in the regulation of specific immune tolerance responsible for suppressed synovial inflammation and matrix destruction. The distant induction and up-regulation of regulatory cytokines and/or cells may contribute to the inhibition of the immune response through blunted infiltration of inflammatory cells to the joint.
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PMID:Oral delivery of group A streptococcal cell walls augments circulating TGF-beta and suppresses streptococcal cell wall arthritis. 983 19

The purpose was to study tumour necrosis factor (TNF)-a, -b and -c microsatellites as potential new susceptibility markers for reactive arthritis (ReA). Fifty-nine patients typed for HLA-B27 were studied for frequencies of TNF microsatellite alleles and compared with allele frequencies determined from 285 random haplotypes and 46 healthy HLA-B27-positive controls. TNFa, -b and -c microsatellite sequences were amplified by the polymerase chain reaction, and the size of the product was defined by an automated sequencer. The frequencies of TNFa6 and -c1 alleles were found to be increased in patients with ReA, whereas TNFa11 and -c2 frequencies were decreased as compared to control haplotypes. The increase in the c1 allele in patients with ReA independently from HLA-B27 suggests that it might be a new susceptibility marker for the disease. The association of ReA with other alleles was due to a linkage disequilibrium with HLA-B27.
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PMID:Tumour necrosis factor microsatellites in reactive arthritis. 985 Dec 70

Am-80 is a newly snythesized retinoid with the structure of one aromatic amide among retinobenzoic acids. It exhibits specific biological activities of retinoic acid such as the activation of cellular differentiation and proliferation. We investigated the effect of Am-80 on collagen-induced arthritis (CIA) in mice and the immunopharmacological action on the production of several cytokines in the in vitro and in vivo models. Am-80, at doses of 0.3, 1 and 3 mg/kg, significantly inhibited the severity and development of the arthritis index, progression of foot pad swelling, bone damage and histopathological alterations. Am-80 also inhibited the production of anti-type II collagen (CII) IgG antibody, but did not affect the delayed-type hypersensitivity (DTH) response in arthritic mice. To determine the inhibitory mechanism of Am-80, we studied the effect of Am-80 on the production of cytokines. Am-80 did not affect the production of IFN-gamma by Th1 cells (1E10.H2 cells) and IL-4 by Th2 cells (D10.G4.1 cells), respectively. Am-80 selectively inhibited bacterial lipopolysaccharide (LPS)-induced IL-6, but not TNF-alpha and IL-1beta, production in mice. Moreover Am-80 inhibited IL-1beta induced IL-6 production and IL-6 mRNA expression in human osteoblast-like cells (MG-63). The inhibition of IL-6 production by Am-80 was due to downregulation of the pretranscription or the transcription of IL-6 in MG 63 cells. These findings suggest that the inhibitory effect of Am-80 on CIA is partially by modulating the production of the proinflammatory cytokine, IL-6.
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PMID:Effect of Am-80, a synthetic derivative of retinoid, on experimental arthritis in mice. 987 34

This communication describes the synthesis and in vitro and in vivo evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. Several of the compounds presented possess low nanomolar IC50's for PDE4 inhibition and excellent in vivo activity for inhibition of TNF-alpha levels in LPS challenged mice (mouse endotoxemia model). Emesis studies (dog) and efficacy in a SCW arthritis model for the most potent PDE4 inhibitors are presented.
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PMID:Orally active indole N-oxide PDE4 inhibitors. 987 75

A recently developed compound, a multivalent guanylhydrazone (CNI-1493) that inhibits TNF-alpha production by suppressing TNF-alpha translational efficiency, was administered in an experimental model of collagen type II-induced arthritis in DA rats. CNI-1493 was injected daily intraperitoneally either before the onset of arthritis or after the establishment of clinical disease. Prophylactic treatment with CNI-1493 significantly prevented or delayed the onset and suppressed the severity of arthritis in a dose-dependent manner. Therapeutic intervention with CNI-1493 in established joint disease also resulted in a significant reduction of clinical signs of arthritis in treated animals. No severe side-effects were noted when animals were treated with daily CNI-1493 doses up to 5 mg/kg. An immunohistochemical study was performed which demonstrated that CNI-1493 led to a reduced expression of TNF-alpha at the site of disease activity. Thus, CNI-1493 with documented inhibitory effects on TNF-alpha synthesis, has proven successful in ameliorating the course of arthritis in CIA. We believe that the use of a compound such as CNI-1493 with a defined mode of action provides a useful tool for dissecting and understanding important pathogenic mechanisms operating in the development of chronic arthritis.
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PMID:Anti-inflammatory effects of a new tumour necrosis factor-alpha (TNF-alpha) inhibitor (CNI-1493) in collagen-induced arthritis (CIA) in rats. 993 18

Immunosuppressive therapy with methotrexate (MTX) has been established as effective treatment for patients with rheumatoid arthritis. To analyse the therapeutic potential and mechanisms of action of MTX, we determined serum cytokine levels and cytokine production by splenic T cells and macrophages in untreated and MTX-treated mice. Furthermore, we assessed the role of MTX in a murine model of experimental arthritis induced by collagen type II (CIA). MTX reduced spontaneous and IL-15-induced tumour necrosis factor (TNF) production by splenic T cells but not by macrophages from healthy mice in vitro in a dose-dependent manner. In contrast, interferon-gamma (IFN-gamma) production was less strikingly reduced and IL-4 production was virtually unaffected. In addition, treatment of healthy mice with MTX in vivo led to reduced TNF serum levels and diminished TNF production by splenic T cells and macrophages. Intraperitoneal administration of MTX prior to the onset of arthritis completely prevented clinical and pathological signs of CIA. This was associated with a striking reduction of TNF production by spleen cells from MTX-treated mice. The role of TNF in MTX-mediated effects on cytokine production was further underlined by the finding that MTX effects on IFN-gamma production were augmented in TNF-transgenic mice but abrogated in mice in which the TNF-alpha gene had been inactivated by homologous recombination. Thus, MTX specifically modulates spontaneous and IL-15-induced TNF-alpha production in mice and prevents experimental murine CIA. These data suggest that TNF production by T cells is an important target of MTX and may serve as a basis to understand and further analyse MTX-mediated mechanisms of immunosuppression in patients with RA.
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PMID:Methotrexate specifically modulates cytokine production by T cells and macrophages in murine collagen-induced arthritis (CIA): a mechanism for methotrexate-mediated immunosuppression. 993 19

Vascular endothelial growth factor (VEGF) is abundant in synovium and synovial fluids, where it probably contributes to vascular permeability and angiogenesis in arthritic joints. To investigate the probable sources of VEGF in synovium, we compared the ability of several cytokines (TGF-beta, platelet-derived growth factor (PDGF), IL-1, tumour necrosis factor (TNF), basic fibroblast growth factor (bFGF) that are associated with arthritis and angiogenesis, to stimulate secretion of VEGF protein by human synovial fibroblasts. TGF-beta was the strongest inducer of VEGF secretion; six times more VEGF was secreted when cells were stimulated by TGF-beta than when stimulated by PDGF or IL-1 for 24 h. TNF-alpha and bFGF did not stimulate any secretion of VEGF. The stimulatory effects of TGF-beta and IL-1 on VEGF secretion were additive. Hypoxic culture alone also stimulated VEGF secretion, but more importantly, hypoxic culture conditions doubled the rate of VEGF secretion stimulated by the cytokines TGF-beta and IL-1. When dermal and synovial fibroblasts were stimulated identically by hypoxia and cytokines (TGF-beta and IL-1), synovial fibroblasts secreted four times more VEGF than did dermal fibroblasts. Thus in rheumatoid arthritis, the capacity of synovial fibroblasts in the hypoxic environment to secrete large amounts of VEGF in response to cytokines such as TGF-beta probably contributes significantly to angiogenesis in the synovium.
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PMID:Hypoxia augments cytokine (transforming growth factor-beta (TGF-beta) and IL-1)-induced vascular endothelial growth factor secretion by human synovial fibroblasts. 993 39

Collagen type II-induced arthritis (CIA) in DBA/1 mice can be passively transferred to SCID mice with spleen B- and T-lymphocytes. In the present study, we show that infection ex vivo of splenocytes from arthritic DBA/1 mice with a retroviral vector, containing cDNA for the soluble form of human p75 receptor of tumour necrosis factor (TNF-R) before transfer, prevents the development of arthritis, bone erosion and joint inflammation in the SCID recipients. Assessment of IgG subclass levels and studies of synovial histology suggest that down-regulating the effector functions of T helper-type 1 (Th1) cells may, at least in part, explain the inhibition of arthritis in the SCID recipients. In contrast, the transfer of splenocytes infected with mouse TNF-alpha gene construct resulted in exacerbated arthritis and enhancement of IgG2a antibody levels. Intriguingly, infection of splenocytes from arthritic DBA/1 mice with a construct for mouse IL-10 had no modulating effect on the transfer of arthritis. The data suggest that manipulation of the immune system with cytokines, or cytokine inhibitors using gene transfer protocols can be an effective approach to ameliorate arthritis.
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PMID:Prevention of collagen-induced arthritis by gene delivery of soluble p75 tumour necrosis factor receptor. 1002 37

Bacteria or bacterial antigen triggering reactive arthritis have been detected in inflamed joint tissue and fluid of patients. Although live yersiniae have not yet been found in joints of patients with Yersinia arthritis, early dissemination and propagation has been proposed. In this study, we investigated the influence of the proinflammatory cytokines interleukin- (IL-) 1beta, tumor necrosis factor-(TNF-) alpha, the Th1 lymphokine interferon- (IFN-) gamma, and the Th2 lymphokine IL-4 on the intracellular survival of Yersinia enterocolitica O.3 in primary human fibroblast cell monolayers as a model for joint tissue. Bacterial titers in infected cells decreased significantly and in a dose-dependent manner following treatment with IL-1beta, TNF-alpha, or IFN-gamma. The bactericidal effects of IL-1beta and TNF-alpha were synergistic. In contrast, IL-4 significantly supported bacterial survival. In addition, IL-4 antagonized in part the bactericidal effect of TNF-alpha and IFN-gamma. Although IL-1beta, TNF-alpha, and IFN-gamma accelerated killing of intracellular yersiniae the ratio of cells containing bacterial antigen did not differ from that in untreated cells. The differential effects of the investigated cytokines on intracellular survival of yersiniae may be of relevance for the development of Yersinia arthritis: enhanced production of IL-4 by synovial tissue may prolong the survival of yersiniae and persistence of antigen, and thus potentiate immune complex formation and inflammation. In conclusion these results show (1) that fibroblasts can take up virulent yersiniae as non-professional phagocytes and (2) that cytokines, found in the joints of patients with Yersinia arthritis, are able to affect the intracellular survival of yersiniae differentially.
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PMID:Effect of cytokines on invasion and survival of Yersinia in primary human fibroblasts. 1020 47


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