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)

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.
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PMID:Targeting TNF alpha for the therapy of rheumatoid arthritis. 776 56

Neutrophil infiltration into inflammatory sites is one of the hallmarks of acute inflammation. Locally produced chemotactic factors are presumed to mediate the sequence of events leading to the infiltration at inflammatory sites. Interleukin-8 (IL-8), a novel leukocyte chemotactic activating cytokine (chemokine), is produced by various types of cells upon stimulation with inflammatory stimuli and exerts a variety of functions on leukocytes, particularly, neutrophils in vitro. However, no definitive evidence has been presented on its role in recruiting and activating neutrophils in the lesions of various types of inflammatory reactions. We administered a highly specific neutralizing antibody against IL-8 in several types of acute inflammatory reactions, including lipopolysaccharide (LPS)-induced dermatitis, LPS/IL-1-induced arthritis, lung reperfusion injury, and acute immune complex-type glomerulonephritis. Anti-IL-8 treatment prevented neutrophil-dependent tissue damage as well as neutrophil infiltration in these conditions. These results suggest that IL-8 plays a causative role in acute inflammation by recruiting and activating neutrophils.
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PMID:Essential involvement of interleukin-8 (IL-8) in acute inflammation. 796 63

We and others have shown that cells obtained from inflamed joints of rheumatoid arthritis (RA) patients produce interleukin-8, a potent chemotactic cytokine for neutrophils (PMNs). However, IL-8 accounted for only 40% of the chemotactic activity for PMNs found in these synovial fluids. Currently, we have examined the production of the novel PMN chemotactic cytokine, epithelial neutrophil activating peptide-78 (ENA-78), using peripheral blood, synovial fluid, and synovial tissue from 70 arthritic patients. RA ENA-78 levels were greater in RA synovial fluid (239 +/- 63 ng/ml) compared with synovial fluid from other forms of arthritis (130 +/- 118 ng/ml) or osteoarthritis (2.6 +/- 1.8 ng/ml) (P < 0.05). RA peripheral blood ENA-78 levels (70 +/- 26 ng/ml) were greater than normal peripheral blood levels (0.12 +/- 0.04 ng/ml) (P < 0.05). Anti-ENA-78 antibodies neutralized 42 +/- 9% (mean +/- SE) of the chemotactic activity for PMNs found in RA synovial fluids. Isolated RA synovial tissue fibroblasts in vitro constitutively produced significant levels of ENA-78, and this production was further augmented when stimulated with tumor necrosis factor-alpha (TNF-alpha). In addition RA and osteoarthritis synovial tissue fibroblasts as well as RA synovial tissue macrophages were found to constitutively produce ENA-78. RA synovial fluid mononuclear cells spontaneously produced ENA-78, which was augmented in the presence of lipopolysaccharide. Immunohistochemical localization of ENA-78 from the synovial tissue of patients with arthritis or normal subjects showed that the predominant cellular source of this chemokine was synovial lining cells, followed by macrophages, endothelial cells, and fibroblasts. Synovial tissue macrophages and fibroblasts were more ENA-78 immunopositive in RA than in normal synovial tissue (P < 0.05). These results, which are the first demonstration of ENA-78 in a human disease state, suggest that ENA-78 may play an important role in the recruitment of PMNs in the milieu of the inflamed joint of RA patients.
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PMID:Epithelial neutrophil activating peptide-78: a novel chemotactic cytokine for neutrophils in arthritis. 808 42

Interleukin 4 (IL4) is a cytokine produced by T cells and mast cells/basophils. IL4 has a key role in IgE production and in the pathogenesis of atopic diseases. Disorders such as rheumatoid arthritis are characterized by increased production of proinflammatory cytokines and reduced production of IL4. Furthermore, rheumatoid T cells are of the TH 1 type, not producing IL4. In contrast, circulating IL4 has been detected in scleroderma patients, whose T cells are of the TH 2 type, producing IL4. Since IL4 inhibits the production of proinflammatory cytokines such as IL1, IL6, TNF alpha and IL8, we hypothesized that a deficit in IL4 production might be related to the pathogenesis of rheumatoid arthritis. Addition of IL4 strongly reduced the production of proinflammatory cytokines and expression of corresponding mRNA by synovial membrane pieces from RA patients. RA synovitis is also associated with marked proliferation of synoviocytes. Studies of synoviocytes showed that IL4 inhibited the growth promoting effect of PDGF and IL1 beta. IL4 also inhibited production of IL6 by juxta-articular bone pieces. IL4 was found to reduce disease activity and progression in various arthritis models. These anti-inflammatory and anti-proliferative properties suggest that IL4 may be of potential clinical value in RA. Conversely, as IL4 induces dermal fibroblasts to secrete collagen, IL4 might be involved in the pathogenesis of scleroderma.
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PMID:[Anti-inflammatory properties of interleukin-4]. 813 3

Macrophages infiltrated into synovium play an important role in joint destruction in inflammatory joint diseases. In this study we focused on the production of monocyte chemoattractant protein-1 (MCP-1), a recently identified monocyte chemotactic protein, by inflammatory synovium. Synovial fluid (SF) from rheumatoid arthritis (RA), osteoarthritis, gout, and traumatic arthritis contained MCP-1. MCP-1 was produced in the synovium of patients with RA and other inflammatory joint disease in in vitro culture systems; differences in the amounts produced were not significant. Synovial MCP-1 production in RA was further investigated. Levels of MCP-1 were significantly correlated with levels of IL-1 beta, IL-6, and IL-8 in the culture supernatants of synovia from RA. Using immunohistochemical techniques, MCP-1 was detected in the lining and sublining cells and in the vascular endothelial cells of rheumatoid synovia. Rheumatoid synovia with active inflammation were stained more intensely by anti-MCP-1 antibody than were those with weak or inactive inflammation. IL-1 beta and TNF-alpha stimulated the expression of MCP-1 mRNA and de novo MCP-1 synthesis by cultured synovial cells. These results suggest the production of MCP-1 by synovium of various inflammatory joint diseases. In rheumatoid synovium, a cytokine network involving MCP-1 and other proinflammatory cytokines (IL-1 beta, IL-6, IL-8, and TNF-alpha) contributes to the immunopathogenesis of RA.
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PMID:Monocyte chemoattractant protein-1 (MCP-1) in inflammatory joint diseases and its involvement in the cytokine network of rheumatoid synovium. 840 45

Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNF alpha, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGF beta and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNF alpha and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNF alpha was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNF alpha was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNF alpha at its apex. This led to the hypothesis that TNF alpha was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNF alpha therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNF alpha antibody have shown marked clinical benefit, verifying the hypothesis that TNF alpha is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNF alpha dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.
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PMID:Role of cytokines in rheumatoid arthritis. 871 20

Leukocyte infiltration into an inflammatory site is one of the pathological hallmarks of inflammatory reaction. Locally produced chemotactic factors are presumed to mediate the sequence of events leading to tissue injury associated with the infiltration of leukocytes. Chemotactic cytokines (chemokines) have been identified as being produced by various types of cells upon stimulation with inflammatory stimuli and exhibit a variety of effects on leukocytes in vitro and in vivo. Administration of highly specific neutralizing antibodies against these chemokines in several types of animal inflammation models clearly suggests important roles of these chemokines in recruiting and activating specific types of leukocytes at the inflammatory sites. Anti-IL-8 Ab treatment prevented neutrophil-dependent tissue damage as well as neutrophil infiltration in lipopolysaccharide (LPS)-induced dermatitis, LPS/IL-1-induced arthritis, lung reperfusion injury, and acute immune complex type glomerulonephritis in rabbits. Moreover, anti-MCP-1 Ab and anti-RANTES Ab inhibited macrophage infiltration in IgA immune complex alveolitis in rats and influx of lung macrophages in a murine model of endotoxemia, respectively. The use of anti-MIP-1alpha Ab also revealed that MIP-1alpha mediates eosinophil infiltration in allergic, granulomatous reactions in vivo.
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PMID:Use of Blocking Antibodies as Probes for in Vivo Functions of Chemokines 881 62

Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8 and tumour necrosis factor (TNF) are believed to be the major pathological mediators of inflammatory diseases ranging from arthritis to the periodontal diseases. The stimuli inducing proinflammatory cytokine induction in the former disease is unclear but in the periodontal diseases it is obvious that the stimulus is the accumulation of bacteria in the subgingival region. As these bacteria do not invade the lesional tissues in large numbers, it is believed that their soluble components or products interact with host tissues to induce cytokine gene transcription. The paradigm is that lipopolysaccharide is the key bacterial component inducing pro-inflammatory cytokine gene expression. However, over the past decade a growing number of reports on non-oral bacteria have established that many other bacterial components, as well as secretory products, have the capacity to induce cytokine synthesis. Some of these, such as the protein pneumolysin from Streptococcus pneumoniae, are incredibly potent (in this case inducing cytokine synthesis at femtomolar concentrations). This review surveys the range of bacterial components and products which have been shown to stimulate cytokine synthesis with particular emphasis on the hypothesis that these components play a role in the pathology of the periodontal diseases.
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PMID:Cytokine-inducing components of periodontopathogenic bacteria. 888 33

To examine the involvement of cytokines in the mechanisms of N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine, MDP-Lys(L18)-induced arthritis, we analyzed interleukin-1 (IL-1), tumor necrosis factor (TNF), colony-stimulating factor (CSF), and neutrophil chemotactic factor (NCF) by bioassays in the rat macrophage-conditioned medium (Mluminal diameter-CM) stimulated by MDP-Lys(L18) in vitro and the synovial fluid from dogs treated subcutaneously with MDP-Lys(L18) for 14 days in vivo. The dog showed arthritis characterized by swelling of the knee joint, increased synovial fluid and thickened synovial membrane, and a single subcutaneous injection of MDP-Lys(L18) was previously shown to induced synovitis in rat tarsal joint. IL-1, TNF, CSF, and NCF activities in Mluminal diameter-CM were increased by MDP-Lys(L18), while only NCF activity was detected in the dog synovial fluid. Partial purification procedures revealed that NCF in Mluminal diameter-CM was not leukotriene B4 but a protein having heparin-affinity, and, in addition, immuno-reactive IL-8 was evident to be in Mluminal diameter-CM. The NCF activity in the dog synovial fluid was not inhibited by dialysis, showing that NCF is a protein substance, possibly a chemokine. These results suggest that MDP-Lys(L18) produces a chemokine, such as IL-8, which recruits neutrophils to the synovial membrane for subsequent development of synovitis in rats and dogs.
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PMID:Inflammatory cytokine production induced by an analogue of muramyl dipeptide MDP-Lys(L18) in rat macrophage cultures and dog synovial fluid. 892 48

The activation of endothelial cells is a recurrent phenomenon linked to pathologic conditions such as inflammation, chronic arthritis, allo- and xenograft rejection. To inhibit endothelial cell activation we have constructed a transactivation-deficient derivative of the p65/RelA subunit of NF-kappa B, a transcription factor known to be crucial for the induction of adhesion molecules, cytokines and procoagulants in activated endothelial cells. This protein (p65RHD) comprises the Rel homology domain of the RelA subunit, retaining dimerization, DNA binding, and nuclear localization functions, but is deficient in transcriptional activation, and acts as a competitive inhibitor of NF-kappa B. Our data demonstrate that p65RHD is a potent and specific inhibitor of NF-kappa B-mediated induction of a number of genes, such as I kappa B alpha, IL-8, E-selectin, P-selectin, and tissue factor in endothelial cells. Furthermore, tetracycline-inducible expression of p65RHD in stably transfected primary endothelial cells inhibits the induction of gene expression equally well. This regulated system of gene expression provides the basis for a novel therapeutic approach to the pathologic effects of endothelial cell activation, especially in delayed xenograft rejection, by using transgenic animals as organ donors.
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PMID:Inhibition of bovine endothelial cell activation in vitro by regulated expression of a transdominant inhibitor of NF-kappa B. 904 81


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