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)

The infiltration of leucocytes into the joint of rheumatoid arthritis (RA) is believed to be mediated by chemotactic factors released by activated cells. In this study, examination was made of the gene expression and production of the chemokine superfamily in RA patients by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoprecipitation. Cultured synovial fibroblasts were found capable of expressing and producing IL-8, GRO, monocyte chemotactic and activating factor (MCAF), macrophage inflammatory protein-1 alpha (MIP-1 alpha), MIP-1 beta and RANTES in response to IL-1 alpha. The expression of IL-8, GRO, MCAF, MIP-1 alpha, and MIP-1 beta was clearly shown to increase in freshly isolated synovial fluid mononuclear cells (SFMC) of RA patients, in contrast to peripheral blood mononuclear cells (PBMC) of RA patients and normal subjects. The gene expression of RANTES appeared to be the same for RA SFMC, RA PBMC, and normal PBMC. Thus, the over-expression of various chemokines may promote the recruitment of inflammatory cells into rheumatoid inflamed joints.
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PMID:Expression of the chemokine superfamily in rheumatoid arthritis. 752 8

Leukocyte recruitment is critical in the inflammation seen in rheumatoid arthritis (RA). To determine whether the chemokine growth-related gene product alpha (gro alpha) plays a role in this process, we examined synovial tissue (ST), synovial fluid (SF), and plasma samples from 102 patients with arthritis. RA SF contained more antigenic gro alpha (mean 5.3 +/- 1.9 ng/ml) than did SFs from either osteoarthritis (OA) or other forms of arthritis (mean 0.1 ng/ml) (p < 0.05). RA plasma contained more gro alpha (mean 4.3 +/- 1.8 ng/ml) than normal plasma (mean 0.1 ng/ml) (p < 0.05). RA ST fibroblasts (1.2 x 10(5)/cells/mI RPMI 1640/24 h) produced antigenic gro alpha (mean 0.2 +/- 0.1 ng/ml), and this production was increased significantly upon incubation with TNF-alpha (mean 1.3 +/- 0.3 ng/ml) or IL-1 beta (mean 2.3 +/- 0.6 ng/ml) (p < 0.05). Cells from RA SF also produced gro alpha: neutrophils (PMNs) (10(7) cells/mI/24 h) produced 3.7 +/- 0.7 ng/ml. RA SF mononuclear cells produced gro alpha, particularly upon incubation with LPS or PHA. Immunoreactive ST gro alpha was found in greater numbers of RA compared with either OA or normal lining cells, as well as in RA compared with OA subsynovial macrophages (p < 0.05). IL-8 accounted for a mean of 36% of the RA SF chemotactic activity for PMNs, while epithelial neutrophil-activating peptide-78 accounted for 34%, and gro alpha for 28%, of this activity. Combined neutralization of all three chemokines in RA SFs resulted in a mean decrease of 50% of the chemotactic activity for PMNs present in the RA SFs. These results indicate that gro alpha plays an important role in the ingress of PMNs into the RA joint.
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PMID:Growth-related gene product alpha. A chemotactic cytokine for neutrophils in rheumatoid arthritis. 756 Oct 66

The aim of this study was to determine whether the cytokine macrophage inflammatory protein-1 beta (MIP-1 beta) is present and functionally active in the arthritic joint. We used immunoassays and bioassays to assess the presence and function of MIP-1 beta using samples obtained from 62 arthritic patients. MIP-1 beta levels were increased in synovial fluids (SFs) from patients with osteoarthritis (OA) (18.0 +/- 8.9 ng/ml) (SD) compared to patients with rheumatoid arthritis (RA) 6.1 +/- 2.9 ng/ml) or other forms of arthritis (10.4 +/- 7.0 ng/ml) (P < 0.05). Levels of OA SF MIP-1 beta were significantly greater than OA or normal serum levels of MIP-1 beta. Anti-MIP-1 beta neutralized 28% of the chemotactic activity for monocytes found in OA SFs. Isolated OA synovial tissue fibroblasts did not constitutively produce MIP-1 beta but could be induced to express this chemokine upon exposure to tumor necrosis factor-alpha, interleukin-1 beta, or lipopolysaccharide. Synovial tissue immunohistochemical staining revealed that the main immunopositive cells in OA were the lining cells as well as vascular smooth muscle and endothelial cells. A minority of macrophages were immunopositive as well. In this study, we identify MIP-1 beta as a unique cytokine increased in OA compared to RA SF. We conclude that MIP-1 beta may play a role in the ingress of monocytes into the OA joint.
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PMID:Macrophage inflammatory protein-1 beta: a C-C chemokine in osteoarthritis. 758 41

A chronic inflammatory disease may be characterized by an accumulation of activated leukocytes at the site of inflammation. Since the chemokine RANTES may play an active role in recruiting leukocytes into inflammatory sites, we investigated the ability of cultured human synovial fibroblasts isolated from patients suffering from rheumatoid arthritis to produce this chemokine and compared its regulation to that of the closely related chemokine gene, interleukin-8 (IL-8). In unstimulated synovial fibroblasts, the expression of mRNA for both chemokines was undetectable, but was increased in both a time- and dose-dependent manner upon stimulation with the monokines tumor necrosis factor alpha (TNF alpha) and interleukin-1 beta (IL-1 beta). Preincubation of the cells with cycloheximide "superinduced" the level of IL-8 mRNA stimulated by TNF alpha and IL-1 beta and RANTES mRNA stimulated by IL-1 beta, but decreased the expression of RANTES mRNA in response to TNF alpha. In addition, differential regulation of these genes was noted when synovial fibroblasts were stimulated with a combination of cytokines. IL-4 down-regulated and IFN gamma enhanced the TNF alpha- and IL-1 beta-induced increase in RANTES mRNA, whereas the induction of IL-8 mRNA by TNF alpha or IL-1 beta was inhibited by IFN gamma and augmented by IL-4. Moreover, a combination of TNF alpha and IL-1 beta synergistically induced IL-8 mRNA expression, whereas under the same conditions, the level of expression of RANTES mRNA was less than that induced by TNF alpha alone. These observations were also reflected at the level of chemokine secretion. These studies demonstrate that by expressing the chemokines RANTES and IL-8, synovial fibroblasts may participate in the ongoing inflammatory process in rheumatoid arthritis. In addition, the observation that these chemokine genes are differentially regulated, depending upon the presence of different cytokines, indicates that the type of cellular infiltrate and the progress of the inflammatory disease is likely to depend on the relative levels of stimulatory and inhibitory cytokines.
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PMID:Expression of the cytokine RANTES in human rheumatoid synovial fibroblasts. Differential regulation of RANTES and interleukin-8 genes by inflammatory cytokines. 768 Jun 48

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

This study analyzes the effects of the T cell cytokines IL-4 and IFN-gamma on the spontaneous and stimulated production of IL-8, MCP-1, IL-1 receptor antagonist (IL-1ra), and PGE by synoviocytes from rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Cells from both sources constitutively released IL-8 and MCP-1, but no IL-1ra or PGE. Stimulation with IL-1 beta or TNF-alpha massively increased chemokine production and induced the generation of PGE and low amounts of IL-1ra. The constitutive or cytokine-stimulated release of IL-8 was inhibited by IFN-gamma, but not by IL-4. The constitutive or IL-1 beta-stimulated release of MCP-1, by contrast, was markedly enhanced by IL-4 and IFN-gamma. Both cytokines, however, had only borderline effects on the release stimulated by TNF-alpha. The yield of IL-1ra was strongly enhanced by IFN-gamma in all cases, whereas the effect of IL-4 was pronounced only in IL-1 beta-stimulated OA synoviocytes. IL-4, on the other hand, markedly decreased the release of PGE, which was less susceptible to IFN-gamma. The observed effects on chemokines, IL-1ra expression, and PGE release by synoviocytes suggest that IFN-gamma and IL-4 are important regulatory elements in the inflamed synovium and may exert anti-inflammatory effects.
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PMID:Production of interleukin-1 receptor antagonist, inflammatory chemotactic proteins, and prostaglandin E by rheumatoid and osteoarthritic synoviocytes--regulation by IFN-gamma and IL-4. 812 Apr 7

1. Rheumatoid arthritis is associated with the accumulation and activation of selected populations of inflammatory cells within the arthritic joint. One putative signal for this process is the production, by resident cells, of a group of inflammatory mediators known as the chemokines. 2. The chemokines interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1) and RANTES (regulated on activation normal T-cell expressed and presumably secreted) are target-cell specific chemoattractants produced by synovial fibroblasts in response to stimulation with interleukin-1 alpha (IL-1 alpha) or tumour necrosis factor alpha (TNF alpha). The signalling pathways involved in their production are not well defined. We therefore used four different protein kinase C inhibitors to investigate the role of this kinase in the regulation of chemokine mRNA and protein expression in human cultured synovial fibroblasts. 3. The non-selective PKC inhibitor, staurosporine (1-300 nM) significantly increased the production of IL-1 alpha-induced IL-8 mRNA and protein. A specific PKC inhibitor, chelerythrine chloride (0.1-3 microM), also caused a small concentration-dependent increase in IL-8 mRNA and protein production. In contrast, 3-[1-[3-(amidinothio)propyl]-3-indoly]-4-(1-methyl-3-indolyl )- 1H-pyrrole-2,5-dione methanesulphonate (Ro 31-8220) and 2[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3- yl)-maleimide (GF 109203X), two selective PKC inhibitors of the substituted bisindolylmaleimide family had a concentration-dependent biphasic effect on IL-1 alpha or TNF alpha-induced chemokine expression. At low concentrations they caused a stimulation in chemokine production, which was especially evident at the mRNA level. At higher concentrations both inhibited IL-1 alpha or TNF alpha-induced chemokine mRNA and protein production. Ro 31-8220 was 10 fold more potent than GF 109203X, with an IC50 of 1.6 +/- 0.08 microM (mean +/- s.e.mean, n = 4) for IL-1 alpha induced IL-8 production. Ro 31-8220 also inhibited the expression of IL-1 alpha or TNF alpha-induced MCP-1 and RANTES mRNA with a similar potency. 4. The stimulatory effect of staurosporine is discussed in relation to the known poor selectivity of this inhibitor for PKC. It is proposed that activation of an isoform of PKC, possibly PKC epsilon or zeta, which is inhibited by higher concentrations of the bisinodolylmaleimides, plays a role in the regulation of chemokine expression induced by IL-1 alpha or TNF alpha in synovial cells. 5. The inhibition of chemokine production by bisindolylmaleimide compounds heralds a novel approach for future anti-inflammatory therapies.
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PMID:Differential effects of protein kinase C inhibitors on chemokine production in human synovial fibroblasts. 888 22

cDNA microarray technology is used to profile complex diseases and discover novel disease-related genes. In inflammatory disease such as rheumatoid arthritis, expression patterns of diverse cell types contribute to the pathology. We have monitored gene expression in this disease state with a microarray of selected human genes of probable significance in inflammation as well as with genes expressed in peripheral human blood cells. Messenger RNA from cultured macrophages, chondrocyte cell lines, primary chondrocytes, and synoviocytes provided expression profiles for the selected cytokines, chemokines, DNA binding proteins, and matrix-degrading metalloproteinases. Comparisons between tissue samples of rheumatoid arthritis and inflammatory bowel disease verified the involvement of many genes and revealed novel participation of the cytokine interleukin 3, chemokine Gro alpha and the metalloproteinase matrix metallo-elastase in both diseases. From the peripheral blood library, tissue inhibitor of metalloproteinase 1, ferritin light chain, and manganese superoxide dismutase genes were identified as expressed differentially in rheumatoid arthritis compared with inflammatory bowel disease. These results successfully demonstrate the use of the cDNA microarray system as a general approach for dissecting human diseases.
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PMID:Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. 912 63

Chemokines such as IFN-inducible protein-10 (IP-10) and JE/monocyte chemotactic protein-1 (MCP-1) are induced in the murine liver in a tissue-specific manner. We examined whether IP-10 and MCP-1 are pathologically involved in chronic hepatitis. Whereas the serum levels of IP-10 and MCP-1 in patients with chronic persistent hepatitis C were elevated compared with those in normal volunteers, both chemokine levels were further significantly higher in patients with the active form (chronic active hepatitis (CAH)). The elevated IP-10 level was not a general phenomenon of inflammation, because it was not seen in patients with rheumatoid arthritis, whereas MCP-1 levels were elevated to the same extent in both patient groups. Better responsiveness to IFN therapy in CAH was related to lesser grades of necroinflammatory activity and was predicted by the lower IP-10 and higher MCP-1 levels. IP-10 levels in patients cured by IFN therapy decreased to the levels in normal volunteers, while the MCP-1 levels only slightly decreased. Serum levels of both chemokines in patients who were not cured remained unchanged after IFN therapy. In situ hybridization analysis of CAH revealed that IP-10 mRNA was expressed mainly in hepatocytes around intralobular focal and periportal piecemeal necrosis, while some MCP-1 mRNA was expressed in some sinusoidal cells. These results suggested that IP-10 plays a specific role in the intralobular accumulation of mononuclear cells and/or the death of hepatocytes in chronic hepatitis.
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PMID:Expression of IFN-inducible protein-10 in chronic hepatitis. 916 78

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


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