Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytokine tumor necrosis factor alpha (TNF alpha) and the growth factor basic fibroblast growth factor (bFGF) are known to induce early response genes such as c-fos and c-jun in various cell types. Activation of AP-1, a heterodimeric complex of Fos and Jun proteins, is required for matrix metalloproteinase production and cell proliferation. However, the signaling pathways by which these two factors influence the expression and activities of AP-1 remain currently poorly characterized. Several studies have shown that cytokines induce reactive oxygen species (ROS) production, but growth factor induction of ROS has not been reported. In the present study we demonstrate that both TNF alpha and bFGF induce ROS production, and that this is a common signaling event involved in the stimulation of c-fos gene expression in chondrocytes. To our knowledge, this is the first report directly demonstrating ROS production upon stimulation with a growth factor. TNF alpha and bFGF induction of ROS production is mediated through flavonoid-containing enzymes such as NADPH oxidase. Moreover, the ROS nitric oxide is not responsible for the induction of c-fos expression by TNF alpha and bFGF. In addition, the inhibitory effects of antioxidants on c-fos expression may account for their protective roles against proliferative and inflammatory diseases such as cancer, cardiovascular diseases, and arthritis.
 ...
PMID:Involvement of reactive oxygen species in cytokine and growth factor induction of c-fos expression in chondrocytes. 774 16

Tumor necrosis factor-alpha (TNF-alpha) is released from a cell membrane-anchored precursor by proteolytic cleavage. We have shown that broad spectrum synthetic inhibitors of matrix metalloproteinases (MMPs) prevent the processing of the TNF precursor but do not inhibit the release of other cytokines. Purified MMPs, stromelysin, matrilysin, collagenase, and the gelatinases can all cleave a recombinant pro-TNF substrate to yield mature TNF. MMP inhibitors prevent the rise in blood levels of TNF after endotoxin administration in rats and are effective in animal models of inflammatory disease such as adjuvant arthritis. Drugs that inhibit MMP action and TNF release show great promise for the treatment of autoimmune inflammatory diseases.
 ...
PMID:Matrix metalloproteinases and processing of pro-TNF-alpha. 775 57

Our pre-clinical studies have demonstrated a pathogenic role for TNF alpha in RA. Firstly, TNF alpha and its receptors are upregulated and co-expressed in the synovium and cartilage-pannus junction of RA joints. Secondly, mononuclear cells from RA joints maintained in culture produce many cytokines with pro-inflammatory activity, including TNF alpha. Neutralizing TNF alpha antibodies in vitro reduces the production of these pro-inflammatory cytokines, including IL-1, IL-8, and GM-CSF. Thirdly, when injected into arthritic DBA/l mice with collagen-induced arthritis, monoclonal anti-TNF antibodies decrease inflammatory damage of joints. Clinical trials employing cA2, a monoclonal chimeric anti-TNF alpha antibody, in open-label and randomized placebo-controlled studies have demonstrated a dose-dependent efficacy with impressive improvement in disease activity and acute phase responses lasting several weeks. We conclude that TNF alpha is a critical mediator of inflammation in RA and is an important therapeutic target in this disease.
 ...
PMID:Targeting TNF alpha for the therapy of rheumatoid arthritis. 776 56

The hyperimmunoglobulinemia D and periodic fever (hyper-IgD) syndrome is typified by recurrent febrile attacks with abdominal distress, joint involvement (arthralgias/arthritis), headache, skin lesions, and an elevated serum IgD level (> 100 U/mL). This familial disorder has been diagnosed in 59 patients, mainly from Europe. The pathogenesis of this febrile disorder is unknown, but attacks are joined by an acute-phase response. Because this response is considered to be mediated by cytokines, we measured the acute-phase proteins C-reactive protein (CRP) and soluble type-II phospholipase A2 (PLA2) together with circulating concentrations and ex vivo production of the proinflammatory cytokines interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF alpha) and the inhibitory compounds IL-1 receptor antagonist (IL-1ra), IL-10, and the soluble TNF receptors p55 (sTNFr p55) and p75 (sTNFr p75) in 22 patients with the hyper-IgD syndrome during attacks and remission. Serum CRP and PLA2 concentrations were elevated during attacks (mean, 213 mg/L and 1,452 ng/mL, respectively) and decreased between attacks. Plasma concentrations of IL-1 alpha, IL-1 beta, or IL-10 were not increased during attacks. TNF alpha concentrations were slightly, but significantly, higher with attacks (104 v 117 pg/mL). Circulating IL-6 values increased with attacks (19.7 v 147.9 pg/mL) and correlated with CRP and PLA2 values during the febrile attacks. The values of the antiinflammatory compounds IL-1ra, sTNFr p55, and sTNFr p75 were significantly higher with attacks than between attacks, and there was a significant positive correlation between each. The ex-vivo production of TNF alpha, IL-1 beta, and IL-1ra was significantly higher with attacks, suggesting that the monocytes/macrophages were already primed in vivo to produce increased amounts of these cytokines. These findings point to an activation of the cytokine network, and this suggests that these inflammatory mediators may contribute to the symptoms of the hyper-IgD syndrome.
 ...
PMID:Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. 778 Jan 42

Pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF alpha) have been implicated in the pathogenesis of rheumatoid arthritis (RA), and have therefore become therapeutic targets. An engineered human antibody, CDP571, that neutralizes human TNF alpha was administered intravenously in single doses of 0.1, 1.0 or 10 mg/kg to patients with active RA (n = 24). The effects of the antibody were compared in a double-blind fashion with those of placebo (n = 12). In an open continuation phase patients were given either 1.0 or 10 mg/kg. We found that CDP571 was well tolerated and caused reductions in markers of disease activity such as erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP): this was confirmed by a reduction in the disease activity score (DAS). There was a reduction in the number of tender joints, maximal in degree and duration after 10 mg/kg. Patients also documented a reduction of pain and relief of arthritis symptoms. The effects of 10 mg/kg CDP571 on ESR, CRP, tender joints, pain and symptom relief compared to placebo were statistically significant at weeks 1 or 2. The continuation phase, although open, confirmed both the safety and the beneficial effects of CDP571 in active RA. In conclusion CDP571, an engineered human anti-TNF alpha antibody, is well tolerated and, after a single dose of 10 mg/kg, provides improvements in symptoms, signs and serological markers of disease activity in patients with active RA.
 ...
PMID:The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody (CDP571) in rheumatoid arthritis. 778 47

The inflammatory cytokines interleukin 1 beta (IL-1 beta) interleukin 6 (IL-6), tumour necrosis factor alpha (TNF alpha) and the anti-inflammatory peptide--the interleukin 1 (IL-1) receptor antagonist--were measured in the plasma of children with juvenile chronic arthritis (JCA). In the two subgroups studied (polyarticular JCA and systemic JCA), there was good correlation between laboratory measures of disease activity C-reactive protein (CRP), erythrocyte sedimentation rate and clinical scores for disease activity. Despite higher levels of CRP in the systemic group IL-1 beta levels were lower and regression analysis recorded a difference in the relationship between CRP and IL-1 beta within the two clinical groups. In contrast, IL-6 levels were high in the systemic group and correlated with disease activity. No such correlation was observed in the polyarticular group. Five children with systemic JCA were studied during the febrile phase of their illness. IL-6 levels rose and fell with the fever. TNF alpha levels also rose and fell but out of phase with the fever. In contrast IL-1 beta levels were either undetectable throughout the febrile episode or only became detectable as the temperature reduced to normal. The IL-1 receptor antagonist was usually found in 1000-fold excess over IL-1 beta, levels rising and falling with the fever. These results demonstrate difference in the cytokine profiles and acute phase protein responses in polyarticular and systemic JCA. This would suggest different pathogenic mechanisms for these two groups of JCA with IL-6 being the more important cytokine in systemic JCA.
 ...
PMID:Inflammatory cytokine responses in juvenile chronic arthritis. 778 76

This review has summarized information published over the last 5 years on the presence and pathophysiologic role of IL-1 and TNF alpha in RA. The evidence to date shows that 5 of 6 criteria for identifying mediators of tissue damage in human autoimmune diseases are satisfied (Table 1). The last criterion, prevention of clinical progression in patients with RA, is currently being evaluated. Many new therapeutic approaches are currently being developed, including the use of soluble receptors to IL-1 or TNF, monoclonal antibodies to TNF alpha, a specific IL-1 receptor antagonist, and gene therapy with the latter molecule. It should be emphasized that both IL-1 and TNF alpha play important roles in normal host defense; the possible complications of blocking their production or effects need to be carefully evaluated in long-term studies. A recent review has emphasized that although IL-1 and TNF alpha have many overlapping biologic properties, each may exhibit distinct effects in joint disease (99). Anti-TNF treatment may be primarily antiinflammatory but blocking IL-1 may be more effective in preventing cartilage destruction (100). The possibility exists that simultaneous inhibition of TNF alpha and IL-1 may be more therapeutically efficacious than blockade of either agent alone, as was recently demonstrated with IL-1ra and soluble TNF receptors in bacterial cell wall-induced arthritis in rats (101). The next level of clinical studies in rheumatoid arthritis should include the use of two biologic response modifiers together, or one agent combined with a more traditional form of therapy.
Arthritis Rheum 1995 Feb
PMID:Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. 784 4

Articular cartilage has important load bearing properties. These depend on the integrity of its matrix which is formed by a dense network of collagen fibres (mainly type II) and a high concentration of proteglycan (mainly aggrecan). The matrix is maintained by the chondrocytes, which control the production and turnover of matrix components and are greatly affected by cytokines (such as IL-1 alpha,beta and TNF alpha) and growth factors (such as IGF-1 alpha, beta TGF beta). They have strongly antagonistic effects. IL-1 alpha, beta and TNF alpha inhibit proteoglycan synthesis and at slightly higher concentration they enhance the rates of matrix degradation. In contrast the growth factor IGF-1 stimulates proteoglycan biosynthesis and reduces matrix proteinase action. TGB beta has less direct anabolic effect on matrix biosynthesis in normal cartilage, but does not induce an anabolic response in isolated chondrocytes or in explants following IL-1 treatment. We have also investigated the action of IL-1 in inflammatory arthritis in vivo by treatment with IL-1 receptor antagonist, the natural IL-1 inhibitor. In antigen-induced arthritis the effects of the injection of rh IL-1 ra was measured over 3 days. There was little effect on the induction of joint swelling, cellular infiltration into synovium or cartilage proteoglycan depletion, but when given over a similar time in more chronic arthritis, 14 days after induction it had a major effect on suppressing synovial fibrosis although it still did not affect parameters of joint inflammation. The results suggested that IL-1 was not the major factor inducing inflammation in the joint, but was responsible for the excessive collagen deposition in the synovium in this experimental model of arthritis.
 ...
PMID:[Regulation of cartilage matrix synthesis by chondrocytes]. 785 13

The mediators involved in leucocyte recruitment to joints during arthritis are not fully defined, but two important proinflammatory cytokines, IL-1 and tumour necrosis factor-alpha (TNF-alpha), are produced in joints in rheumatoid arthritis (RA). We investigated in the rat adjuvant arthritis model whether endogenous IL-1 and TNF-alpha contribute to joint inflammation and polymorphonuclear leucocyte (PMNL) and T lymphocyte infiltration. The migration of 51Cr-labelled rat blood PMNL and 111In-labelled T lymphocytes to the joints of rats with adjuvant arthritis was measured along with plasma protein extravasation, which was quantified using 125I-labelled human albumin. Rats with active arthritis of 5 days' duration received i.p. non-immune serum, polyclonal neutralizing anti-serum to rat TNF-alpha, antiserum to IL-1 alpha and IL-1 beta, or both anti-TNF plus anti-IL-1 for 5 days. Treatment with anti-IL-1 alpha and IL-1 beta did not affect plasma protein extravasation, or PMNL or T lymphocyte accumulation in the joints (i.e. talar joint, hind paws, and tail) despite the fact that this treatment inhibited 80-90% of the PMNL migration into dermal sites injected with IL-1 alpha or IL-1 beta. In contrast, anti-TNF-alpha treatment significantly improved clinical scores, decreased plasma protein extravasation by 60-80%, inhibited PMNL accumulation by 40-50% and decreased T lymphocyte accumulation by 30-50%. Treatment with anti-IL-1, together with anti-TNF-alpha, significantly potentiated the inhibition of T lymphocyte accumulation observed with anti-TNF-alpha alone. These results indicate that endogenous TNF-alpha production may play an important role in the inflammatory changes and leucocyte recruitment in this experimental model of human arthritis, while IL-1 may have a less important role in leucocyte recruitment to these joints.
 ...
PMID:The role of tumour necrosis factor-alpha and IL-1 in polymorphonuclear leucocyte and T lymphocyte recruitment to joint inflammation in adjuvant arthritis. 803 15

Recombinant human cytokines were examined for their effects on plasminogen activator inhibitor-1 (PAI-1) production by human articular cartilage and chondrocyte monolayer cultures. Cartilage and chondrocytes were cultured with and without added cytokines and the conditioned media assayed for PAI-1 by a specific enzyme-linked immunosorbent assay, and mRNA levels determined by Northern blot analysis. Tumor necrosis factor alpha (TNF alpha) reduced, and transforming growth factor-beta (TGF-beta) and basic fibroblast growth factor (bFGF) increased, the levels of PAI-1 antigen and mRNA in the culture fluids and cell extracts, respectively. The effects of TNF alpha and TGF-beta on PAI-1 antigen levels were both time- and concentration-dependent; optimum doses being 10-100 pM TNF alpha and 0.4-0.8 nM TGF-beta, with each cytokine exerting its effect on PAI-1 antigen levels within 8 h of addition to culture. TNF alpha (and interleukin-1 alpha) also countered the effects of TGF-beta and bFGF. The anti-inflammatory drugs, indomethacin and dexamethasone, did not appear to modulate PAI-1 levels in cultures of cartilage tissue. The inhibition of PAI-1 levels by cytokines and reagents which stimulate cartilage resorption (i.e., TNF alpha, interleukin-1 alpha, retinoic acid) and enhancement by cytokines which counter it (i.e., TGF-beta, bFGF) further implicate plasminogen activator in the mechanism(s) of cartilage degradation in diseases such as arthritis.
 ...
PMID:Cytokine modulation of plasminogen activator inhibitor-1 (PAI-1) production by human articular cartilage and chondrocytes. Down-regulation by tumor necrosis factor alpha and up-regulation by transforming growth factor-B basic fibroblast growth factor. 805 59


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>