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)

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

An antagonist of human monocyte chemoattractant protein (MCP)-1, which consists of MCP-1(9-76), had previously been characterized and shown to inhibit MCP-1 activity in vitro. To test the hypothesis that, by inhibiting endogenous MCP-1, the antagonist has antiinflammatory activity in vivo, we examined its effect in the MRL-lpr mouse model of arthritis. This strain spontaneously develops a chronic inflammatory arthritis that is similar to human rheumatoid arthritis. Daily injection of the antagonist, MCP-1(9-76), prevented the onset of arthritis as monitored by measuring joint swelling and by histopathological evaluation of the joints. In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist. In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction in symptoms and histopathology, although individuals varied in the magnitude of the response. The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro. The demonstration of the beneficial effects of an MCP-1 antagonist in arthritis suggests that chemokine receptor antagonists could have therapeutic application in inflammatory diseases.
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PMID:An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model. 920 7

Chemokines are small proteins that selectively activate and recruit leukocytes to sites of inflammation. Several of them, including the CC chemokines RANTES, MIP-1 alpha, MIP-1 beta, MCP-1, and the CXC chemokines IL-8, GRO-alpha, ENA-78 have been identified in rheumatoid synovium, implicating a potential role for these molecules in rheumatoid arthritis. We have investigated the expression patterns of CC chemokine receptors in the joints of mice with collagen-induced arthritis, a model for human rheumatoid arthritis. In addition, we have investigated the incidence and severity of arthritis in mice receiving administration of MetRANTES, a modified chemokine which is a nanomolar antagonist of certain CC chemokine receptors. The mRNA expression pattern of the chemokines and their receptors in the joints of arthritic mice was investigated using reverse transcriptase-PCR and in situ hybridization. An upregulation of the CC chemokine receptors mCCR1, mCCR2; mCCR3 and mCCR5 was found in the joints from arthritic mice, compared to control animals. In addition, injections of MetRANTES reduced the incidence of disease in a dose dependent manner. Furthermore, in MetRANTES-treated mice that did develop arthritis a significantly lower severity of disease was observed compared with control animals. Our data clearly demonstrate a role for CC chemokines and their receptors in inflammatory joint destruction and support the use of chemokine receptor antagonists as potential tools to control inflammatory diseases such as rheumatoid arthritis.
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PMID:Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. 923 36

As an alternative to classical immunosuppressants in experimental lupus nephritis, we looked at bindarit, 2-methyl-2-[[1-phenylmethyl)-1H-indazol-3-y1]methoxy]propanoic acid, a novel molecule devoid of immunosuppressive effects, which selectively reduces chronic inflammation in rat adjuvant arthritis. Two groups of NZB/W mice (N = 55 for each group) were given bindarit, (50 mg/kg/day p.o.) or vehicle starting at 2 months of age. Mice were sacrificed at 2, 6, 8 and 10 months or used for survival studies. Bindarit delayed the onset of proteinuria (% proteinuric mice, bindarit vs. vehicle, 6 months: 0 vs. 33% and 8 months: 7% vs. 60%, P < 0.005; 10 months: 53% vs. 80%) and significantly (P < 0.05) protected from renal function impairment (serum BUN, bindarit vs. vehicle: 8 months, 30 +/- 3 vs. 127 +/- 42; 10 months, 53 +/-5 vs. 140 +/- 37 mg/dl). Appearance of anti-DNA antibodies was retarded and survival significantly (P < 0.0001) prolonged by bindarit (% survival, bindarit vs. vehicle: 8 months, 100% vs. 80%; 10 months, 87% vs. 40%; 12 months, 27% vs. 20%). Bindarit significantly limited glomerular hypercellularity, interstitial inflammation and tubular damage. Renal expression of monocyte chemoattractant protein (MCP-1) mRNA (Northern blot) markedly increased (7 - 12-fold in 8- 10-month-old mice vs. 2-month-old) during the progression of nephritis in association with mononuclear cell infiltration. Bindarit completely prevented MCP-1 up-regulation. In another series of experiments, bindarit (0.25% and 0.5% medicated diet, N = 16 for each group) when started at 4.5 months of age in NZB/W mice improved survival in respect to untreated mice (N = 17) in a dose-dependent manner (% survival: 8 months, 94% and 100%, respectively, vs. 47%; 10 months, 75% and 100% vs. 35%; 12 months, 31% and 75% vs. 12%). Survival was even more prolonged when bindarit (0.5% medicated diet) was combined with a low dose of methylprednisolone (1.5 mg/kg i.p.), which that only partially modifies proteinuria and survival of lupus mice, in an additional group of animals (N = 16). Thus, at 14.5 months when all mice given bindarit alone died, 50% of mice on combined therapy were still alive (P < 0.023). Studies are needed to establish whether bindarit may function as a steroid sparing drug in human lupus.
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PMID:Bindarit retards renal disease and prolongs survival in murine lupus autoimmune disease. 950 20

Since IL-8 and MCP-1 are chemoattractant proteins that participate in the recruitment of inflammatory cells into the arthritic joint, we examined the effects of tenidap, a new anti-inflammatory drug of the oxindole family, on IL-8 and MCP-1 expression in the joints of rabbits with acute antigen arthritis. The model was induced by injecting 5 mg/ml ovalbumin into the knees of 20 preimmunized rabbits. Animals were randomized into two groups: treated with tenidap (15 mg/kg per 12 h), or untreated. The effect of tenidap treatment was evaluated on chemokine production in synovial membranes of rabbits with arthritis and in cultured monocytic and synovial cells (SC). By immunoperoxidase staining, chemokines were localized in the synovial tissue. Chemokine messenger RNA levels in the synovial membranes and in cultured cells were analysed by reverse transcription-polymerase chain reaction (RT-PCR). At the end of the study, tenidap significantly reduced neutrophil infiltration into the joint cavity (27+/-4 x 10(6) cells/ml versus 45+/-6 x 10(6) cells/ml in untreated; P<0.05), and synovial effusion (134+/-15 microl versus 236+/-19 microl in untreated; P<0.005). Untreated rabbits showed synovial membrane up-regulation in mRNA expression of IL-8 and MCP-1 (11- and seven-fold versus healthy rabbits, respectively) that was markedly decreased by tenidap (two- and three-fold versus healthy rabbits, respectively). IL-8 and MCP-1 were localized in the synovial tissue in a perivascular pattern and areas of the interstitium and lining, mostly coinciding with cell infiltration. Tenidap also reduced the accumulation of IL-8 and MCP-1 proteins. In cultured synovial and monocytic cells, tumour necrosis factor-alpha (TNF-alpha) elicited an increase in gene expression of IL-8 (four- and nine-fold, respectively) and MCP-1 (nine- and four-fold, respectively) that was significantly reversed in both cell types by 10 microM tenidap. These results suggest that the beneficial effect of tenidap in acute antigen arthritis could be related to the down-regulation in gene expression and synthesis of IL-8 and MCP-1, two key chemokines involved in the recruitment of inflammatory cells.
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PMID:Tenidap decreases IL-8 and monocyte chemotactic peptide-1 (MCP-1) mRNA expression in the synovial tissue of rabbits with antigen arthritis and in cultured synovial cells. 952 4

We investigated the inflammatory processes that might be associated with the arthrogenic activity of Staphylococcus aureus, the principal causative agent of bacterial arthritis. Human peripheral blood mononuclear cells (PBMC) were stimulated with the staphylococcal toxic shock syndrome toxin-1 (TSST-1) or enterotoxin B (SEB) and the production of chemokines was examined. Both TSST-1 and SEB induced high levels (ng/mL) of MIP-1alpha, MIP-1beta, and MCP-1. The induction of these chemokines occurred mostly by direct stimulation of PBMC with staphylococcal exotoxins (SE), without requiring the intervention of IL-1 and TNF-alpha. The production of SE-induced chemokines was blocked partially by anti-DR and anti-CD2 antibodies. Cell separation revealed monocytes as the cell source of these chemokines. However, addition of purified T cells amplified the levels of chemokine produced, suggesting that cognate interaction of SE bound on antigen-presenting cells with T cells also contributes to chemokine production. The activation and recruitment of leukocytes by these chemokines may contribute to the pathophysiology of septic arthritis caused by staphylococci in humans through tissue injury and the recruitment of T lymphocytes, perhaps also initiating autoimmune responses. Pentoxifylline, an anti-inflammatory agent, completely inhibited the production of these chemokines.
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PMID:Induction of CC chemokines in human peripheral blood mononuclear cells by staphylococcal exotoxins and its prevention by pentoxifylline. 1041 Oct 4

Depending on the method of immunization, a single administration of CFA may result in the development of a local inflammatory process or chronic polyadjuvant-induced arthritis (AA). We administered naked DNA vaccines encoding MIP-1 alpha, MCP-1, MIP-1 beta, and RANTES to Lewis rats and confirmed that each of these vaccines induced immunological memory to the corresponding gene product. Upon induction of disease, this memory effectively inhibited the development of the autoimmune condition. Self-specific Ab's developed in DNA-vaccinated animals were neutralizing in vitro and could adoptively transfer the beneficial effect of each vaccine. Repeated administration of the constructs encoding MCP-1, MIP-1 alpha, or RANTES inhibited the development and progression of AA, even when each vaccine was administered only after the onset of disease. This suggests a highly effective way by which the immune system could be re-educated to generate protective immunity against its own harmful activities.
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PMID:C-C chemokine-encoding DNA vaccines enhance breakdown of tolerance to their gene products and treat ongoing adjuvant arthritis. 1093 Apr 39

We analyzed the effects of the new antirheumatic drug KE-298 on monocyte chemoattractant protein (MCP)-1 and regulated on activation normal T-cell expressed and secreted (RANTES) production in rats with adjuvant-induced arthritis and in interleukin (IL)-1beta-stimulated rheumatoid arthritis (RA) synoviocytes. In rats with adjuvant-induced arthritis, the enhanced production of MCP-1 and RANTES and the development of arthritis were suppressed by oral treatment with 100 mg/kg per day of KE-298 for 18 days. Furthermore, KE-298 (10-100 microg/ml) suppressed MCP-1 and RANTES production by IL-1beta-stimulated RA synoviocytes through inhibition of NF-kappaB and AP-1 activation. These results suggest that the inhibitory effect of KE-298 on MCP-1 and RANTES production might partly explain its efficacy in rats with adjuvant-induced arthritis and in patients with RA.
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PMID:The new antirheumatic drug KE-298 suppresses monocyte chemoattractant protein (MCP)-1 and RANTES production in rats with adjuvant-induced arthritis and in IL-1beta-stimulated synoviocytes of patients with rheumatoid arthritis. 1141 59

Chemokines are mediators of innate and acquired immunity. CCL18, also designated pulmonary and activation-regulated chemokine (PARC), dendritic cell-derived CC chemokine-1 (DC-CK1), alternative macrophage activation-associated CC chemokine-1 (AMAC-1) and macrophage inflammatory protein-4 (MIP-4), was for the first time isolated from peripheral blood mononuclear cells (PBMC) and biochemically characterized. We found that CCL18/PARC protein is spontaneously secreted by PBMC and is selectively induced in PBMC by staphylococcal enterotoxins (SEA, SEB) and IL-4, but not by IFN-gamma and the CXCL8/IL-8 inducers lipopolysaccharide (LPS) or Concanavalin A. Human fibroblasts, chondrocytes and endothelial cells did not produce CCL18/PARC in response to inflammatory mediators such as measles virus, double-stranded RNA, LPS or IL-1beta, whereas up to 150 ng/ml of CCL2/MCP-1 was induced under these conditions. In synovial fluids from septic and rheumatoid arthritis patients, fourfold-enhanced CCL18/PARC levels (150 ng/ml) were detected compared to those in crystal-induced arthritis and osteoarthritis. In septic arthritis, the synovial levels of CCL18/PARC were fivefold higher than those of CXCL8/IL-8. Immunochemistry revealed CD68(+) monocytes/macrophages as the main CCL18/PARC-producing cell type in both PBMC and arthritic synovial tissue. In addition, CD1a(+) blood dendritic cells expressed CCL18/PARC. These findings suggest that monocytic cells respond to Gram-positive bacterial infection by the production of CCL18/PARC in the synovial cavity.
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PMID:Selective induction of CCL18/PARC by staphylococcal enterotoxins in mononuclear cells and enhanced levels in septic and rheumatoid arthritis. 1174 96

Chemokines belong to a large family of structurally related proteins that play a pivotal role in immune system development and deployment. While a large number of chemokines (approximately 50) and their receptors (approximately 20) have been identified from humans or mice, only a few are known in domestic veterinary species. Recent data implicate CXCL8 (old name, IL-8), CXCL10 (old name, IP-10) (both CXC chemokines) and CCL2 (old name, MCP-1) (a CC chemokine) in veterinary infections, inflammatory diseases or reproduction. There is compelling evidence for neutrophil targeting chemokines such as CXCL8, in ovine bacterial mastitis, bovine pneumonic pasturellosis and equine chronic obstructive pulmonary disease (COPD). Monocyte and lymphocyte targeting chemokines appear to play a role in caprine arthritis encephalitis (CCL2) and canine endotoxemia (CXCL10). Interestingly CCL2 is considered a missing link between hormonal and cellular control of luteolysis. On the other hand, canine cardiovascular conditions are associated with overexpression of CCL2 and CXCL8. Furthermore, a number of veterinary viral pathogens encode chemokine/chemokine receptor like molecules or chemokine binding proteins that may help viruses to evade the immune system. Here, we provide an overview of the chemokine system and critically evaluate the current literature implicating chemokines in veterinary pathophysiology. Furthermore, we highlight promising areas for further research and discuss how and why chemokine antagonists are viewed as next generation anti-inflammatory drugs for the 21st century.
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PMID:Chemokines in health and disease. 1200 79


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