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)

Interferon-gamma is a cytokine which is believed to play a role in both the susceptibility and pathogenesis of lupus. To determine whether genetic variants might influence the development of this polygenic autoimmune disease, we analyzed the gene frequency of eight different alleles in controls and patients with SLE. Ninety-nine controls and 136 patients with systemic lupus erythematosus were genotyped for a CA repeat in the first intron of the interferon-gamma gene. There were no statistically significant differences in the allele frequencies between patients and controls suggesting that these polymorphic variants do not influence susceptibility. We then examined whether any of these alleles were associated with specific clinical manifestations. Allele 1 was associated with gastrointestinal lupus while allele 6 was associated with more severe lupus. Allele 2 appeared to be protective for arthritis. This suggests that genetic variation in interferon-gamma expression might influence the disease course.
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PMID:Interferon-gamma polymorphisms in systemic lupus erythematosus. 1152 17

Prodigiosin (PDG) was previously reported to be a T cell-specific immunosuppressant. Here we describe the mechanism of action of PDG in T cells and the effect of PDG on autoimmune diseases. PDG selectively suppresses concanavalin A (Con A)-induced T cell proliferation, but has little effect on lipopolysaccharide-induced proliferation of B cells and nitric oxide production of macrophages. Although PDG does not block interleukin (IL)-2 production, it efficiently inhibits interleukin-2 receptor alpha-chain (IL-2Ralpha) expression, and this results in a disruption of the IL-2/IL-2R signaling pathway, on which a great part of the regulation of T cell activation depends. PDG blocks T cell differentiation into effector helper T cells secreting interferon-gamma and IL-4 as well as into effector cytotoxic T lymphocytes expressing perforin, which is at least in part resulting from inhibition of the IL-2/IL-2R signaling. PDG indirectly blocks signal transducer and activator of transcription activation by inhibiting cytokine signalings in Con A-activated T cells, although it does not inhibit the activation of nuclear factor-kappaB, nuclear factor of activated T cells, and activator protein-1. As direct evidence of immunosuppression in vivo, we show that PDG markedly reduced blood glucose levels and cellular infiltration into the pancreatic islets in nonobese diabetic mice, and that it also delays the onset of collagen-induced arthritis in DBA/1 mice. In conclusion, our results demonstrate that PDG has a unique mode of action, namely, that it blocks T cell activation by inhibiting primarily IL-2Ralpha expression in the IL-2/IL-2R signaling, and show that this compound represents a promising immunosuppressant candidate for the treatment of autoimmune diseases.
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PMID:Prodigiosin blocks T cell activation by inhibiting interleukin-2Ralpha expression and delays progression of autoimmune diabetes and collagen-induced arthritis. 1160 50

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs worldwide owing to their anti-inflammatory, antipyretic and analgesic properties. However, their use is hampered by gastrointestinal (GI) toxicity, the most common drug-related serious adverse event in industrialised nations. Nitric oxide (NO)-releasing NSAIDs, a recently described class of drugs, are generated by adding a nitroxybutyl or a nitrosothiol moiety to the parent NSAID via a short-chain ester linkage. While efficacy of nitrosothiol-NO-NSAIDs still awaits investigation, nitroxybutyl-NO-NSAIDs have been extensively studied in animals, thus the abbreviation NO-NSAIDs used here refers to the latter group of NSAID derivatives. NO-NSAIDs retain the anti-inflammatory and antipyretic activity of original NSAIDs, although they exhibit markedly reduced gastrointestinal toxicity. NO-NSAIDs are nonselective cyclo-oxygenase (COX) inhibitors, and they also exert COX-independent activities that are NO-dependent. Indeed, NO-NSAIDs suppress production of the cytokines interleukin (IL)-1beta, IL-18 and interferon-gamma by causing the S-nitrosilation/inhibition of caspase-1. In acute and chronic animal models of inflammation, it has been demonstrated that NO-NSAIDs abrogated prostaglandin E2 as well as thromboxane B2 generation. In a murine model, NO-naproxen was approximately 10-fold more potent than naproxen in reducing animal writhing after intraperitoneal injection of acetic acid. Similar data have been obtained in chronic models of pain such as rat adjuvant arthritis. In vivo and in vitro studies suggest that NO-aspirin (acetylsalicylic acid) exerts more potent antithrombotic action than aspirin, probably by coupling the ability to inhibit COX-1 with the anti-adhesive effect of NO. Moreover, in a model of renal injury NO-flurbiprofen not only has been demonstrated to be devoid of nephrotoxicity but also to ameliorate renal function. Finally, in an animal model of chronic neurodegenerative disease, NO-flurbiprofen and NO-aspirin attenuated the brain inflammatory response. The GI toxicity of NO-flurbiprofen and NO-naproxen is currently being investigated in healthy individuals.
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PMID:Nitric oxide-releasing NSAIDs: a review of their current status. 1166 68

Bone loss represents a major unsolved problem in rheumatoid arthritis (RA). The skeletal complications of RA consist of focal bone erosions and periarticular osteoporosis at sites of active inflammation, and generalized bone loss with reduced bone mass. New evidence indicates that osteoclasts are key mediators of all forms of bone loss in RA. TNF-alpha is one of the most potent osteoclastogenic cytokines produced in inflammation and is pivotal in the pathogenesis of RA. Production of tumor necrosis factor-alpha (TNF-alpha) and other proinflammatory cytokines in RA is largely CD4(+) T-cell dependent and mostly a result of interferon-gamma (IFN-gamma) secretion. Synovial T cells contribute to synovitis by secreting IFN-gamma and interleukin (IL)-17 as well as directly interacting with macrophages and fibroblasts through cell-to-cell contact mechanisms. Activated synovial T cells express both membrane-bound and soluble forms of receptor activator of NF-kappaB ligand (RANKL). In rheumatoid synovium, fibroblasts also provide an abundant source of RANKL. Furthermore, TNF-alpha and IL-1 target stromal-osteoblastic cells to increase IL-6, IL-11, and parathyroid hormone-related protein (PTHrP) production as well as expression of RANKL. In the presence of permissive levels of RANKL, TNF-alpha acts directly to stimulate osteoclast differentiation of macrophages and myeloid progenitor cells. In addition, TNF-alpha induces IL-1 release by synovial fibroblasts and macrophages, and IL-1, together with RANKL, is a major survival and activation signal for nascent osteoclasts. Consequently, TNF-alpha and IL-1, acting in concert with RANKL, can powerfully promote osteoclast recruitment, activation, and osteolysis in RA. The most convincing support for this hypothesis has come from in vivo studies of animal models. Protection of bone in the presence of continued inflammation in arthritic rats treated with osteoprotegerin (OPG) supports the concept that osteoclasts mediate bone loss, providing further evidence that OPG protects bone integrity by downregulating osteoclastogenesis and promoting osteoclast apoptosis. Modulation of the RANKL/OPG equilibrium in arthritis may provide additional skeletal benefits, such as chondroprotection. The nexus between T-cell activation, TNF-alpha overproduction, and the RANKL/OPG/RANK ligand-receptor system points to a unifying paradigm for the entire spectrum of skeletal pathology in RA. Strategies that address osteoclastic bone resorption will represent an important new facet of therapy for RA.
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PMID:Involvement of receptor activator of NFkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis. 1185 40

Human tumour necrosis factor (TNF)-like weak inducer of apoptosis (hTWEAK) and two anti-hTWEAK mAbs were tested for their ability to elicit or block inflammatory responses in cultured human dermal fibroblasts and synoviocytes. Incubation with hTWEAK increased the production of prostaglandin E2, matrix metalloproteinase-1 (MMP-1), IL-6, and the chemokines IL-8, RANTES (regulated on activation, normal T expressed and secreted) and interferon-gamma-inducible protein-10 (IP-10) in culture supernatant of fibroblasts and synoviocytes. In combination with TNF or IL-1beta, hTWEAK further stimulated the secretion of prostaglandin E2, MMP-1, IL-6 and IL-8 up to fourfold, and IP-10 and RANTES up to 70-fold compared to TNF or IL-1beta alone. An anti-hTWEAK mAb, BCB10, blocked the effects of hTWEAK, whereas hTWEAK crosslinked by the anti-hTWEAK mAb, BEB3, further stimulated the inflammatory response of fibroblasts and synoviocytes. The anti-hTWEAK mAbs were ineffective in blocking or increasing the responses of TNF or IL-1beta and blocking anti-TNF mAb was ineffective in preventing the responses to TWEAK. These results were also confirmed at the RNA level for MMP-1, macrophage chemoattractant protein-1, RANTES, macrophage inflammatory protein-1alpha, IP-10 and IL-8. TWEAK in synergism with IL-1 and TNF may be an additional cytokine that plays a role in destructive chronic arthritic diseases.
Arthritis Res 2002
PMID:Proinflammatory activity of TWEAK on human dermal fibroblasts and synoviocytes: blocking and enhancing effects of anti-TWEAK monoclonal antibodies. 1187 48

The plasminogen activators, urokinase PA (u-PA) and tissue-type PA (t-PA), are believed to play important roles in inflammatory cell infiltration, fibrin deposition, and joint destruction associated with rheumatoid arthritis; however, their precise roles in such processes, particularly u-PA, have yet to be defined. Using gene-deficient mice we examined the relative contribution of the PAs to the chronic systemic collagen-induced arthritis model. Based on clinical and histological assessments, u-PA-/- mice developed significantly milder disease and t-PA-/- mice more severe disease compared with the relevant wild-type mice. Fibrin deposition within joints paralleled disease severity and was particularly pronounced in t-PA-/- mice. Likewise, cytokine levels in the synovium reflected the severity of disease, with interleukin-1beta levels in particular being lower in u-PA-/- mice and increased in t-PA-/- mice. The antibody response to type II collagen was normal in both knockouts; however, T cells from u-PA-/- mice had a reduced proliferative response and produced less interferon-gamma on antigen stimulation in vitro. These results indicate that the major effect of u-PA in the collagen-induced arthritis model is deleterious, whereas that of t-PA is protective. Our data highlight the complexities of PA function, and suggest that approaches either to target u-PA or to enhance local t-PA activity in joints may be of therapeutic benefit in rheumatoid arthritis.
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PMID:Differing roles for urokinase and tissue-type plasminogen activator in collagen-induced arthritis. 1189 Nov 90

Fluorinated quinolones exert their bactericidal activity by inhibiting bacterial type II topoisomerases. At therapeutic concentrations, quinolones superinduce interleukin-2 (IL-2) and interferon-gamma production by mitogen-activated human peripheral blood T lymphocytes. At the molecular level, a stronger activation of the nuclear factor AP-1 ('activator protein-1') is observed in cells incubated with ciprofloxacin, resulting in enhanced cytokine gene transcription. Several cytokine and immediate early (e.g., c-fos and c-jun) mRNAs are upregulated by ciprofloxacin, possibly reflecting a mammalian stress response. In cultures with murine splenocytes, quinolones enhance IL-3 and granulocyte-macrophage colony stimulating factor (GM-CSF) synthesis. The stimulation of these hematopoietic growth factors prolongs survival of mice with depressed bone marrow and prevents experimental antiphospholipid syndrome (APS). In contrast, quinolones inhibit both human and mouse monocytic IL-1 and TNF-alpha synthesis, an effect that is beneficial in rat experimental type II collagen induced arthritis and LPS-induced septic chock in mice. The intriguing immunomodulatory activities of fluoroquinolones warrant future investigations with new tailored derivatives.
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PMID:Immunomodulating activity of quinolones: review. 1189 96

Increased severity of disease and persistence of symptoms have been recently reported in some patients with simultaneous infection of Borrelia burgdorferi and Babesia microti in the northeastern and northern midwest United States. This study used a murine model to examine whether defined disease conditions such as arthritis and carditis differed in severity in mice infected solely with B. burgdorferi and in mice coinfected with B. microti and B. burgdorferi. C3H.HeJ and BALB/c mice cohorts were coinfected or singly infected and then monitored experimentally for 15 and 30 days after inoculation. Carditis and arthritis was determined by blinded histopathologic evaluation of myocardium and tibiotarsal joints. Cytokine measurements were made on lymph node and spleen supernatants for interferon-gamma, interleukin (IL)-4, IL-10, and IL-13. No differences were observed for C3H.HeJ mice cohorts; however, coinfected BALB/c mice had a significant increase in arthritis severity at day 30. This clinical observation was correlated with a significant reduction in expression of the cytokines IL-10 and IL-13.
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PMID:Increased arthritis severity in mice coinfected with Borrelia burgdorferi and Babesia microti. 1213 42

Previous reports have demonstrated the ability of antigen-presenting cells (APCs), genetically modified to express Fas ligand (FasL), to inhibit T-cell responses through the induction of apoptosis of antigen-specific T cells. Here we have examined the ability of primary mouse bone marrow-derived dendritic cells (DCs), genetically modified by adenoviral infection to express FasL, to inhibit progression of established collagen-induced arthritis (CIA) in DBA/1 mice. Systemic injection of DC/FasL into mice with established CIA resulted in substantial disease amelioration as determined by analysis of paw swelling, arthritic index, and number of arthritic paws. Moreover, a single injection of DC/FasL resulted in extended suppression of disease. We also demonstrate that treatment of arthritic mice with DC/FasL suppressed interferon-gamma (IFN-gamma) production from spleen-derived lymphocytes and reduced T-cell proliferation following collagen stimulation without affecting the levels of anti-collagen antibody isotypes. These results demonstrate that systemic administration of DC/FasL is able to suppress collagen-reactive T cells, resulting in effective and sustained treatment of established CIA.
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PMID:Effective treatment of established mouse collagen-induced arthritis by systemic administration of dendritic cells genetically modified to express FasL. 1240 56

The effects of a monoclonal antibody (MoAb DB-1), which neutralized rat interferon-gamma (IFN-gamma), on the induction and progression of adjuvant arthritis in Lewis rats induced by intraplantar injection of Freund's complete adjuvant was studied. The animals were treated intraperitoneally with MoAb DB-1 (0.3-5 mg) for various times. Prophylactic treatment with MoAb DB-1, starting 2 days prior to arthritis induction, inhibited oedema in both the injected and non-injected hind paws and delayed joint destruction as shown by radiography. However, despite continued MoAb treatment, the disease progressed. High doses of MoAb DB-1 exacerbated the disease. A control MoAb of the same isotype did not have significant effects on adjuvant arthritis. Therapeutic treatment with the MoAb DB-1 starting 8 days after arthritis induction caused only slight and short-lived inhibitory effects. IFN-gamma appears to be a critical lymphokine for the development of adjuvant arthritis.
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PMID:Suppression and augmentation of rat adjuvant arthritis with monoclonal anti-interferon-gamma antibody. 1241 57


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