Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0003873 (rheumatoid arthritis)
53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We used the severe combined immunodeficient (SCID) mouse model to assess the effect of interleukin-4 (IL-4) or IL-10 injection on cartilage degradation and mononuclear cell (MNC) recruitment to human rheumatoid synovium in vivo. Human rheumatoid synovium and cartilage from five rheumatoid arthritis patients, obtained after joint replacement surgery, were engrafted subcutaneously to 6-8-week-old SCID CB17 mice. Synovial tissues were injected with recombinant human IL-4 (rhIL-4, 100 ng; rhIL-10, 100 ng), both cytokines, or tumour necrosis factor-alpha (TNF-alpha) (1000 U), or phosphate-buffered saline twice a week for 4 weeks. The graft was removed and immunochemical analysis was carried out to assess intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin expression. Moreover, cartilage degradation was assessed through the quantification of the erosion surface on a computerized image of the engrafted cartilage at high power view. MNC recruitment in the synovial tissue was determined by labelling blood MNC with indium-111 before their intraperitoneal injection. The activity obtained in the region of the graft were determined with a gamma camera 72 hr postinjection. The results are expressed as a percentage of initial injected activity. After 4 weeks we observed a decrease of cartilage area in controls (77 +/- 8%), inhibited after injection of IL-4, IL-10, or both cytokines (90 +/- 3%, 89.1 +/- 4%, 89.2 +/- 5% respectively), and 57 +/- 17% after TNF-alpha injection. The % MNC activity in the graft decreased to 77 +/- 81% (NS), 9 +/- 4% (P < 0.003) and 19 +/- 6% (P < 0.007) compared with untreated synovial tissue after treatment with IL-4, IL-10, or both cytokines, respectively. Moreover, IL-10 but not IL-4 decreased the expression of ICAM-1 but not VCAM-1 or E-selectin by synovial cells. These results suggest that IL-10 and IL-4 could have chondroprotective properties, and that IL-10 but not IL-4 inhibits MNC traffic towards the synovial tissue efficiently.
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PMID:Interleukin-4 and interleukin-10 are chondroprotective and decrease mononuclear cell recruitment in human rheumatoid synovium in vivo. 965 24

R6.5 (BIRR-1, Enlimomab), a murine IgG2a mAb to the human ICAM-1, inhibits leukocyte adhesion to the vascular endothelium, thereby decreasing leukocyte extravasation and inflammatory tissue injury. In initial clinical trials, R6.5 proved to be beneficial in reducing both disease activity in refractory rheumatoid arthritis and the incidence of acute rejection after kidney and liver allograft transplantations. However, adverse effects such as fever, leukopenia, or cutaneous reactions were not infrequent. We studied the effects of R6.5 on neutrophil function in whole blood samples ex vivo. Surprisingly, at the concentrations achieved in clinical trials, R6. 5 activated neutrophilic granulocytes, as indicated by a significant increase in expression of the adhesion molecule beta2-integrin CD11b, a concurrent decrease in L-selectin expression, and an enhancement of the oxidative burst activity. Neutrophil activation was not exerted by an anti-ICAM-1 mAb of the IgG1 isotype, by isotype-matched, irrelevant anti-2-phenyloxazolone mAb, or by F(ab')2 fragments of R6.5. Neutrophil activation was completely inhibited by soluble complement receptor type 1. We conclude that in whole blood, R6.5 activates resting neutrophils in a complement-dependent manner. This finding can explain, at least in part, the side effects associated with R6.5 therapy.
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PMID:Anti-ICAM-1 monoclonal antibody R6.5 (Enlimomab) promotes activation of neutrophils in whole blood. 997 15

Both infiltrating leukocytes and soluble immunoglobulin form aggregates in synovial fluid during the inflammatory process in rheumatoid arthritis (RA). Some of these changes are probably mediated by the adhesion molecule, E-selectin, which increases its expression with disease activity. As glycosylation changes in IgG in RA are well established, the current study was undertaken to measure the expression of the carbohydrate antigen sialyl Lewis x (sLe(x)), on IgG in RA. sLe(x) is a major ligand for E-selectin. Using a recently developed ELISA, sLe(x) expression was determined in IgG isolated from 8 healthy individuals, 20 RA sufferers (10 early and 10 with more long-standing disease) and 20 patients with other rheumatic conditions (osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus). S Le(x) expression on IgG was elevated above the reference range in all but one of the RA patients and this change was highly significant (P < 0.0006). Expression of this antigen on IgG was also significantly different from normal in the other arthritic groups (P < 0.02), but the changes were much less than that observed for RA. In early RA, sLe(x) was inversely correlated with parameters used to measure disease activity. This was not observed with the established RA, where there was weak positive association. These preliminary results indicate that a change in sLe(x) expression on IgG is an early finding in the development of RA, which may be important in the development of the disease or for predicting its outcome.
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PMID:Sialyl Lewis(x) expression on IgG in rheumatoid arthritis and other arthritic conditions: a preliminary study. 1037 70

The aim of this work was to determine differences in pro- and anti-inflammatory cytokine and adhesion molecule expression in synovial tissue from patients with rheumatoid arthritis (RA) or osteoarthritis (OA). Synovial tissue samples were obtained from patients with RA and OA, and from healthy individuals. The expression of mRNA of interleukin (IL)-1beta, IL-4, IL-6, IL-8, IL-10, IL-13, tumour necrosis factor-alpha (TNF-alpha) and transforming growth-factor-beta1 (TGF-beta1) was evaluated by the polymerase chain reaction (PCR). In addition, IL-8 and IL-10 transcripts were measured by quantitative PCR. The expression of IL-8 and IL-10 proteins was determined by immunoperoxidase staining. To evaluate the inflammatory stage of synovial tissue, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) protein expression was also determined. RA patients were found to display higher levels of adhesion molecules than patients with OA. PCR analysis showed a similar profile of cytokine transcripts between the OA and RA groups. Gene expression of IL-4 and IL-13 in synovium was undetectable. In contrast, IL-1beta, IL-6, IL-8, IL-10, TNF-alpha and TGF-beta1 transcripts were expressed by both groups. Increased levels of IL-8 and IL-10 transcripts and their proteins were observed in synovium from RA patients when compared to patients with OA and healthy controls. Thus, our data show that IL-8, IL-10, ICAM-1 and VCAM-1 expression levels are higher in synovial tissue from patients with RA than in similar tissue from patients with OA.
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PMID:Interleukin-8, interleukin-10, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression levels are higher in synovial tissue from patients with rheumatoid arthritis than in osteoarthritis. 1044 28

An early event in acute and chronic inflammation and associated diseases such as atherosclerosis and rheumatoid arthritis is the induced expression of specific adhesion molecules on the surface of endothelial cells (ECs), which subsequently bind leukocytes. Peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor superfamily of transcription factors, are activated by fatty acid metabolites, peroxisome proliferators, and thiazolidinediones and are now recognized as important mediators in the inflammatory response. Whether PPAR activators influence the inflammatory responses of ECs is unknown. We show that the PPAR activators 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), Wyeth 14643, ciglitazone, and troglitazone, but not BRL 49653, partially inhibit the induced expression of vascular cell adhesion molecule-1 (VCAM-1), as measured by ELISA, and monocyte binding to human aortic endothelial cells (HAECs) activated by phorbol 12-myristate 13-acetate (PMA) or lipopolysaccharide. The "natural" PPAR activator 15d-PGJ(2) had the greatest potency and was the only tested molecule capable of partially inhibiting the induced expression of E-selectin and neutrophil-like HL60 cell binding to PMA-activated HAECs. Intracellular adhesion molecule-1 induction by PMA was unaffected by any of the molecules tested. Both PPAR-alpha and PPAR-gamma mRNAs were detected in HAECs by using reverse transcription-polymerase chain reaction and a ribonuclease protection assay; however, we have yet to determine which, if any, of the PPARs are mediating this process. These results suggest that certain PPAR activators may help limit chronic inflammation mediated by VCAM-1 and monocytes without affecting acute inflammation mediated by E-selectin and neutrophil binding.
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PMID:Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction. 1047 50

The measurement of leukocyte rheology in vascular disease is a recent development with a wide range of new opportunities. The International Society of Clinical Hemorheology has asked an expert panel to propose guidelines for the investigation of leukocyte rheology in clinical situations. This article first discusses the mechanical, adhesive and related functional properties of leukocytes (especially neutrophils) which influence their circulation, and establishes the rationale for clinically-related measurements of parameters which describe them. It is concluded that quantitation of leukocyte adhesion molecules, and of their endothelial receptors may assist understanding of leukocyte behaviour in vascular disease, along with measurements of flow resistance of leukocytes, free radical production, degranulation and gene expression. For instance, vascular cell adhesion molecule (VCAM-1) is abnormally present on endothelial cells in atherosclerosis, diabetes mellitus and inflammatory conditions. Soluble forms of intercellular adhesion molecule (ICAM-1) or VCAM can be found elevated in the blood of patients with rheumatoid arthritis or infections disease. In the second part of the article, possible technical approaches are presented and possible avenues for leukocyte rheological investigations are discussed.
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PMID:Measurement of leukocyte rheology in vascular disease: clinical rationale and methodology. International Society of Clinical Hemorheology. 1051 84

In rheumatoid arthritis (RA) the adhesion molecule ICAM-1 mediates the adhesion of leucocytes following subsequent transendothelial migration including interactions and adhesion of several cell types such as fibroblasts, T-lymphocytes and synoviocytes. Significantly increased ICAM-1 levels were measured in the acute phase of RA. The correlation of ICAM-1 levels with the pteridine neopterin (p < or = 0.01) may reflect the role of this adhesion molecule in modulation of immune responses. Despite the significantly higher levels of acute phase reactions parallel to the elevated ICAM-1 levels, no correlations were found between ICAM-1 and erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum-Amyloid A (SAA). During an in-patient multidisciplinary rehabilitation programme the levels of ICAM-1 in serum and the majority of all investigated laboratory and clinical parameters such as ESR, CRP, SAA, fibrinogen, pain, swollen and painful joint count, morning stiffness and health assessment questionnaire improved.
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PMID:[Adhesion molecule ICAM-1 in patients with chronic polyarthritis--effects of inpatient rehabilitation]. 1063 65

Amyloidosis refers to the extracellular accumulation of amyloid fibrils, derived from a circulating precursor, in various tissue and organs. The most common form of amyloidosis worldwide is that which occurs secondary to chronic inflammatory disease, particularly rheumatoid arthritis. The precursor molecule is serum amyloid A (SAA), an acute phase reactant, which can be used as a surrogate marker of inflammation in many diseases. SAA has a number of immunomodulatory roles, can induce chemotaxis and adhesion molecule expression, has cytokine-like properties and can promote the upregulation of metalloproteinases. It enhances the binding of high density lipoprotein to macrophages and thus helps in the delivery of lipids to sites of injury for use in tissue repair. It is thus thought to be an integral part of the disease process. Moreover, elevated levels of SAA over time predispose to secondary amyloidosis. Pathogenic factors underlying this disease are outlined along with guidelines for diagnosis and management.
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PMID:Amyloid precursors and amyloidosis in rheumatoid arthritis. 1065 43

VLA-4 is a critical adhesion molecule that regulates mononuclear cell trafficking to sites of inflammation. VCAM-1 is a primary ligand of VLA-4, although alternatively spliced fibronectin (FN) containing the CS1 region (CS1 FN) also binds to VLA-4. CS1 FN is expressed by rheumatoid arthritis (RA) synovial endothelial cells, but the factors that regulate CS1 FN expression are not known. We incubated human umbilical vein endothelial cells (HUVEC) with IL-1 (0.1-10 ng/ml) for 8-48 h and determined total FN and CS1 FN mRNA by Northern blot analysis. Both were constitutively expressed by HUVEC, and IL-1 increased total FN mRNA and the CS1-containing isoform (P < 0.05). IL-1 also increased CS1 FN protein expression on HUVEC as determined by Western blot analysis. An adhesion assay using (51)Cr-labeled Jurkat cells and IL-1-stimulated HUVEC was used to determine if IL-1-induced CS1 FN mediates cell binding. Cyclic CS1 peptide (10 microg/ml) blocked 49 +/- 5% of IL-1-induced Jurkat cell adhesion to HUVEC (P < 0.01), whereas anti-VCAM-1 antibody inhibited binding by only 35 +/- 5% (P < 0.01). CS1 peptide and anti-VCAM antibody treatment were not additive (50 +/- 7% inhibition), and 38 +/- 6% of new VLA-4-mediated adhesion to IL-1-treated HUVEC was due to an increase in CS1 FN. These data show that IL-1 increases CS1 FN expression by HUVEC and increases CS1-mediated cell adhesion. CS1 mimetics might have therapeutic efficacy by blocking recruitment of VLA-4-bearing cells.
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PMID:Regulation of CS1 fibronectin expression and function by IL-1 in endothelial cells. 1071 77

Beside lymphocytes and neutrophils, eosinophils are also involved in the inflammatory reaction in rheumatoid arthritis (RA). In this study, adhesion characteristics of peripheral blood eosinophils were studied in 43 RA patients and 19 controls, together with the expression of the beta2-integrin Mac-1 (CD11b/CD18). In addition, the production of oxygen radicals of isolated peripheral blood eosinophils and serum levels of eosinophil cationic protein (ECP) were measured in order to evaluate eosinophil activation. Adhesion of eosinophils to unstimulated human vascular endothelium was significantly higher in RA patients with active disease (n = 4) compared with controls (n = 14) (P < 0.005) and compared with patients with less active RA (n = 16) (P < 0.05). Nevertheless, the expression of the adhesion molecule Mac-1 (CD11b/CD18) was not increased in RA patients. ECP levels were higher in RA patients with active disease (P < 0.01). Release of oxygen radicals in response to phorbol stimulation was significantly elevated in active RA compared with controls (P < 0.05) and to less active RA (P < 0.05). We conclude that eosinophils of RA patients, especially those with active disease, are activated or at least primed and are involved in the inflammatory process in RA, analogous to the inflammation in asthma. The higher adhesion to inflamed endothelium is indicative of a higher infiltration in the joints, where tissue damage can be caused by toxic oxygen radicals and by granular proteins, such as ECP.
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PMID:Study of eosinophil-endothelial adhesion, production of oxygen radicals and release of eosinophil cationic protein by peripheral blood eosinophils of patients with rheumatoid arthritis. 1078 Aug 95


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