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)

Interleukin-18 (IL-18) is a novel proinflammatory cytokine found in serum and joints of patients with rheumatoid arthritis (RA). We studied a novel role for IL-18 in mediating cell adhesion, a vital component of the inflammation found in RA and other inflammatory diseases. We examined the expression of cellular cell adhesion molecules E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) on endothelial cells and RA synovial fibroblasts using flow cytometry. Adhesion of the monocyte-like cell line HL-60 to endothelial cells was determined by immunofluorescence. IL-18 significantly enhanced ICAM-1 and VCAM-1 expression on endothelial cells and RA synovial fibroblasts. In addition, IL-18 induced E-selectin expression on endothelial cells and promoted the adhesion of HL-60 cells to IL-18-stimulated endothelial cells. Neutralizing anti-VCAM-1 and anti-E-selectin could completely inhibit HL-60 adherence to endothelial cells. IL-18-induced adhesion molecule expression appears to be mediated through nuclear factor kappa B (NF kappa B) and phosphatidyl-inositol 3 kinase (PI 3-kinase) since addition of inhibitors to either NF kappa B (pyrrolidine dithiocarbamate and N-acetyl-l-cysteine) or PI 3-kinase (LY294002) inhibited RA synovial fibroblast VCAM-1 expression by 50 to 60%. Addition of both inhibitors resulted in inhibition of VCAM-1 expression by 85%. In conclusion, the ability of IL-18 to induce adhesion molecule expression on endothelial cells and RA synovial fibroblasts indicates that IL-18 may contribute to RA joint inflammation by enhancing the recruitment of leukocytes into the joint. IL-18 requires NF kappa B as well as PI 3-kinase to induce VCAM-1 on RA synovial fibroblasts, suggesting that there may be two distinct pathways in IL-18-induced adhesion molecule expression.
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PMID:A novel role for interleukin-18 in adhesion molecule induction through NF kappa B and phosphatidylinositol (PI) 3-kinase-dependent signal transduction pathways. 1147 2

Interleukin-18 (IL-18) is a novel proinflammatory cytokine that was recently found in synovial fluids and in synovial tissues from patients with rheumatoid arthritis (RA). To determine the participation of IL-18 in the inflammation observed in RA, we investigated the effect of IL-18 on RA synovial fibroblast chemokine production. Using FACS analysis, we showed that IL-18 induced a doubling in the production of intracellular IL-8 by RA synovial fibroblasts, and this result was confirmed by Western blot. At the extracellular level, IL-18 up-regulated the secretion of IL-8 in a dose- and time-dependent manner. IL-18 also up-regulated the other CXC chemokines, epithelial-neutrophil activating protein (ENA-78) and growth-regulated oncogene (groalpha), in a dose dependent manner, but failed to induce the production of the CC chemokine, macrophage inflammatory protein (MIP)-1alpha. By immunofluorescence and Western blot, we demonstrated that IL-18 activates the translocation of the transcription factor nuclear factor kappa B (NFkappaB) into the nucleus of RA synovial fibroblasts. IL-18 induces IL-8 secretion through NFkappaB because RA synovial fibroblasts pretreated with antisense to NFkappaB p65 oligonucleotide produce a mean of 44% less IL-8 compared with cells pretreated with the control sense oligonucleotide. These results indicate a novel role for IL-18 in inducing RA synovial fibroblast expression of CXC chemokines through NFkappaB and place this cytokine in a strategic role in the local inflammation observed in RA.
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PMID:Interleukin-18 induces rheumatoid arthritis synovial fibroblast CXC chemokine production through NFkappaB activation. 1159 50

Rheumatoid arthritis (RA) is a chronic arthritic condition that can lead to deformities and disabilities. Although numerous studies reported the association of human leukocyte antigen (HLA)-DRB1*04 and RA, other genes, e.g. cytokines genes, may contribute towards disease susceptibility. Interleukin-18 (IL-18) is a proinflammatory cytokine postulated to play a role in the acute and chronic inflammatory phases of RA. The IL-18 protein expression seems to be regulated by two single-nucleotide polymorphisms (SNPs) located at positions -607 and -137 in the promoter region of the gene. It is postulated that specific alleles may be associated with susceptibility to the development of RA. In the present study, we described the IL-18 gene promoter region genotypes and combined genotypes (-607/-137) in 106 RA patients and 273 unrelated healthy controls to evaluate the contributions of these alleles to RA predisposition in Chinese, Malays, and Indians. The genotyping were performed using sequence-specific polymerase chain reactions. Rheumatoid factors were assayed by enzyme-linked immunosorbent assay. Biodata were obtained through chart review. The controls had significantly higher frequency of AA genotype at position -607 when compared to RA patients. No significant differences were observed in the distribution of either allelic or genotypic frequencies at position -137. There was no association between the genotypes and the presence of rheumatoid factors. This study did not find evidence of a genetic susceptibility factor but demonstrated the novel finding that the AA genotype at position -607 is associated with a protective effect against development of RA in Chinese individuals. This protection may be mediated through inhibition of cyclic (Adenosine 3', 5'-cyclic monophosphate) AMP-responsive element (CRE)-binding protein by the disruption of the CRE consensus sequence.
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PMID:Single-nucleotide polymorphisms of the interleukin-18 gene promoter region in rheumatoid arthritis patients: protective effect of AA genotype. 1461 33

Interleukin-18 (IL-18) is a novel proinflammatory cytokine that was recently found in synovial fluids and synovial tissues from patients with rheumatoid arthritis (RA). To investigate the role of IL-18 in rheumatoid synovitis, the levels of IL-18 and serum amyloid A (SAA) were measured in synovial fluids from 24 patients with rheumatoid arthritis (RA) and 13 patients with osteoarthritis (OA). The levels of IL-18 and SAA in the synovial fluids were elevated in RA patients. In contrast, the levels of IL-18 in synovial fluids from OA patients were significantly lower compared to those of RA patients. SAA was not detected in synovial fluids from OA patients. The expression of SAA mRNA in rheumatoid synovial cells was also examined. SAA4 mRNA, which was constitutively expressed by rheumatoid synovial cells, was not affected by IL-18 stimulation. Although acute phase SAA (A-SAA, SAA1 + 2) mRNA was not detected in unstimulated synovial cells, its expression was induced by IL-18 stimulation. By immunoblot, we demonstrated that IL-18 induced the SAA protein synthesis from rheumatoid synovial cells in a dose-dependent manner. These results indicate a novel role for IL-18 in rheumatoid inflammation through the synovial SAA production.
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PMID:Interleukin-18 induces serum amyloid A (SAA) protein production from rheumatoid synovial fibroblasts. 1473 10

Interleukin-18 is a member of the interleukin-1 family of cytokines with pro-inflammatory and tumor-suppressive properties. Its ability to potently enhance the production of interferon-gamma indicates in particular the crucial function of interleukin-18 as an immunomodulatory molecule. In fact, high levels of interleukin-18 are detected in human diseases associated with immunoactivation including viral or bacterial infections and chronic inflammation. Animal models suggest suppression of interleukin-18 bioactivity as a novel therapeutic concept specifically for the treatment of chronic inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Here we introduce into the biology of interleukin-18 and review immunopharmacological strategies that aim at reducing interleukin-18 bioactivity in human disease.
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PMID:Interleukin-18 bioactivity: a novel target for immunopharmacological anti-inflammatory intervention. 1546 21

Interleukin-18 (IL-18) and its inducer IL-12 have multiple biological activities that are important in generating Th1 responses and inflammatory tissue damage. We investigated serum concentration of the novel proinflammatory Th1 cytokine; IL-18, and its inducer IL-12 in patients with immune rheumatic diseases. Group I comprised32 patients of systemic lupus erythmatosus (SLE), Group II comprised 36 patients of rheumatoid arthritis (RA). Group III comprised 9 patients (2 patients of Behcet, 2 patients of Dermatomyositis, 2 patients of Sicca syndrome, one patient of Scleroderma, and 2 patients of Mixed connective tissue disease). Group IV is a control group consists of 21 sex and age matched healthy subjects and correlated their levels with autoantibody concentration (ANA and ds-DNA), clinical grades and SLE disease activity index (SLEDAI). Serum IL-18, IL-12, ANA and ds-DNA were measured by enzyme immuno sorbent assay. IL-18, IL-12 and ANA were significantly higher in the three studied groups than in the control group (IL-18; P < 0.001 in the three groups, IL-12; P = 0.019, P = 0.002, and P = 0.006, and ANA; P < 0.001, P = 0.002,and P = 0.006, respectively).ds-DNA was significantly higher in SLE patients than in control group (P < 0.001). There were significant positive correlations between; A) levels of IL-18,and both ANA and ds-DNA in SLE patient (r = 0.41,P = 0.001, r = 0.58 and P=0.001 respectively); and B) IL-18 and ANA in both RA and group III patients (r = 0.32, P = 0.005, r = 0.61and P = 0.022 respectively). Also, there were significant positive correlation between the levels of IL-18 and clinical grades of the three groups (r = 0.60,P = 0.001, r = 0.79,P = 0.001, r = 0.78 and P= 0.001 respectively). In SLE patients , IL-18 concentration shows significant positive correlation with SLEDAI score (r = 0.76, P = 0.001). In conclusion, the elevation of proinflammatory cytokines (IL-18 and IL-12 ) may trigger the inflammatory process in immune rheumatic diseases and IL-18 is correlated with disease activity
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PMID:Proinflammatory cytokines (IL-12 and IL-18) in immune rheumatic diseases: relation with disease activity and autoantibodies production. 1571 8

Interleukin-18 (IL-18), a member of the IL-1 family, is known to play a relevant role in rheumatoid arthritis (RA) physiopathology mainly by promoting the inflammatory response. The aim of this work was to investigate the possible implication of two single-nucleotide polymorphisms (SNPs) [-607 A/C (rs1946518) and -137 G/C (rs187238)] within the IL-18-promoter region in RA predisposition and clinical course. A total of 362 unrelated RA patients and 339 healthy controls were genotyped using a real-time polymerase chain reaction (PCR) method for the -607 A/C SNP and a sequence-specific PCR method (PCR-SSP) for the -137 G/C polymorphism. No statistically significant differences were observed for both -607 and -137 IL-18-promoter polymorphisms between RA patients and controls, considering either allelic or genotypic frequencies. In addition, no association was found with the haplotypes inferred by the two polymorphisms and RA susceptibility. This was also the case when RA patients were stratified according to sex, age at the onset of the disease, rheumatoid factor status, and extraarticular manifestations. Our data suggest that -607 A/C (rs1946518) and -137 G/C (rs187238) polymorphisms within the IL-18-promoter region do not play a major role in RA predisposition.
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PMID:Interleukin-18-promoter polymorphisms are not relevant in rheumatoid arthritis. 1589 2

Interleukin-18 (IL-18) is a novel pro-inflammatory cytokine which has been implicated to play a pathogenic role in rheumatoid arthritis (RA). Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis in rheumatoid synoviocytes. In present study, we examined the effect of IL-18 on VEGF production in fibroblast-like synoviocytes (FLS) isolated from the patients with RA. FLS were prepared from the synovial tissues of patients with RA and osteoarthritis (OA) and cultured in the presence of IL-18. The production of VEGF from FLS was measured in culture supernatants by enzyme-linked immunosorbent assay (ELISA). The VEGF messenger RNA (mRNA) expression and AP-1 binding activity of VEGF transcript were determined by reverse transcription-polymerase chain reaction (RT-PCR) and electrophoretic mobility shift assay (EMSA). IL-18 and VEGF levels of sera and synovial fluids (SF) of RA patients (n=30) were significantly higher than those of OA patients (n=20). IL-18 dose-dependently increased the production of VEGF. The effect of IL-18 on VEGF production appeared to be as potent as IL-1beta, whereas tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma showed little effects on VEGF production. AP-1-specific inhibitor Curcumin dose-dependently abrogated the effect of IL-18 on VEGF production. The VEGF enhancement of IL-18 was associated with increased AP-1 binding activity to the VEGF promoter site. These findings suggest IL-18 as an angiogenic factor in RA and down-regulation of IL-18 activity or AP-1 signal pathway can be potential therapeutic targets for RA.
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PMID:Interleukin-18 induces the production of vascular endothelial growth factor (VEGF) in rheumatoid arthritis synovial fibroblasts via AP-1-dependent pathways. 1636 50

Interleukin-18 is a cytokine member of the IL-1 super family that seems to exert powerful Th1-promoting activities in synergy with IL-12. Here we describe the participation of IL-18 in inflammatory joint diseases, in particular rheumatoid arthritis, adult onset Still's disease and juvenile idiopathic arthritis. The emphasis of this study was to summarize in vivo and in vitro studies that focused the action of this pro-inflammatory cytokine on the arthritic process as well as its role in the complex network of chemical mediators involved.
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PMID:Interleukin-18 in chronic joint diseases. 1731 18

Rheumatoid arthritis (RA) is a chronic arthritic condition that can lead to deformities and disabilities. Interleukin-18 (IL-18) is a proinflammatory cytokine known to play a role in the acute and chronic inflammatory phases of RA. IL-18 binding protein is the natural antagonist of IL-18 protein. We aim to identify the effect of HLA-DRB1*04 gene polymorphisms on IL-18 and IL-18BP gene expressions profiles as well as the time-course profiles following in vitro stimulation with mitogens. Peripheral blood mononuclear cells from 16 RA patients and 21 healthy controls were cultured for 1, 4, 8, 12, 24, 48 and 72 h following stimulation with either LPS or PHA. mRNA expression of IL-18 and IL 18BP were determined by quantitative real-time PCR using a comparative Ct (threshold cycle) method. IL-18 levels in supernatants were measured by enzyme-linked immunosorbent assay. Basal mRNA (4.5-fold) and protein levels of IL-18 were increased and IL-18BP mRNA expression was decreased (8-fold) in RA patients when compared to controls. Similarly, increased IL-18 levels were observed in active RA patients, whereas IL-18BP expression was increased in inactive patients. There was an increase in mRNA and protein levels of IL-18 in RA patients that peaked at 4 h and 8 h respectively following LPS stimulation. A similar profile was observed for IL-18BP; however, the expression level was higher in controls than RA patients. Persistent high production of IL-18 in RA is associated with disease progression and IL-18 BP seems to inhibit this activity.
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PMID:HLA-DRB1*04 gene polymorphisms and expressions profiles of interleukin-18 and interleukin-18 binding protein following in vitro stimulation in human peripheral blood mononuclear cells of healthy individuals and patients with rheumatoid arthritis. 1736 19


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