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)

The role of fibroblasts in inflammatory processes and their cross-talk with T cells is increasingly being recognized. Our aim was to explore the capacity of dermal fibroblasts to produce inflammatory chemokines potentially involved in fibrosis occurring in response to contact with polarized human T cells. Our findings indicate that the program of chemokine production by fibroblasts is differentially regulated depending on the T-helper (Th) cell subset used to activate them. Thus, Th1 and Th2 cells preferentially induced production of IFN-gamma inducible protein (IP)-10 and IL-8, respectively, whereas monocyte chemoattractant protein (MCP)-1 was equally induced by both subsets at mRNA and protein levels. Neutralization experiments indicated that membrane-associated tumour necrosis factor-alpha and IL-1 played a major role in the induction of IL-8 and MCP-1 by Th1 and Th2 cells, whereas membrane-associated IFN-gamma (present only in Th1 cells) was responsible, at least in part, for the lower IL-8 and higher IP-10 production induced by Th1 cells. The contributions of tumour necrosis factor-alpha, IL-1 and IFN-alpha were confirmed when fibroblasts were cultured separated in a semipermeable membrane from living T cells activated by CD3 cross-linking. We observed further differences when we explored signal transduction pathway usage in fibroblasts. Pharmacological inhibition of c-Jun N-terminal kinase and nuclear factor-kappaB resulted in inhibition of IL-8 mRNA transcription induced by Th1 cells but not that by Th2 cells, whereas inhibition of MEK/ERK (mitogen-activated protein kinase of extracellular signal-regulated kinase/extracellular signal-regulated kinase) and nuclear factor-kappaB resulted in inhibition of MCP-1 mRNA induced by Th2 but not by Th1 cells. Finally, no distinct differences in chemokine production were observed when the responses to T cell contact or to prototypic Th1 and Th2 cytokines were examined in systemic sclerosis versus normal fibroblasts. These findings indicate that fibroblasts have the potential to participate in shaping the inflammatory response through the activation of flexible programs of chemokine production that depend on the Th subset eliciting their response.
Arthritis Res Ther 2006
PMID:Polarized subsets of human T-helper cells induce distinct patterns of chemokine production by normal and systemic sclerosis dermal fibroblasts. 1635 98

The chemokine receptor, CCR2, is predominantly expressed on monocytes/macrophages, and on a subset of memory T cells. It binds to several CC type chemokines of the monocyte chemoattractant protein (MCP) family of which MCP-1 exhibits the highest affinity. CCR2/MCP-1 expression/association in monocyte/macrophage/T cells has been associated with inflammatory processes such as rheumatoid arthritis, multiple sclerosis and atherosclerosis. Neutralization of CCR2 with either a peptide or receptor antagonist results in the prevention of joint swelling in rodent models of arthritis. In this paper, bioassay-guided discovery of CCR2 receptor antagonists derived from natural product extracts are reported. These antagonists belong to two main classes exemplified by bisthiodiketopiperazines and cytochalasins. Six compounds, including emestrin, two new emestrin analogs, and chaetomin represent the first group of compounds. These compounds inhibited the binding of MCP-1 to CCR2 (CHO membrane) with IC50 values of 0.8 to 9 microM and exhibited good activity in a whole cell assay using MCP-1 and human monocytes with IC50's ranging from 4-9 microM. Cytochalasins A and B represented the second group and inhibited the binding activity with IC50 values of 5 and 188 microM, respectively. This is the first report of natural product antagonists of the CCR2 receptor.
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PMID:Isolation and structures of novel fungal metabolites as chemokine receptor (CCR2) antagonists. 1646 22

Mycoplasma can establish latent infections and are associated with arthritis, leukemia, and chronic lung disease. We developed an experimental model in which lung cells are deliberately infected with Mycoplasma fermentans. Human lung fibroblasts (HLF) were exposed to live M. fermentans and immune-modulating cytokine release was assessed with and without known inducers of cytokine production. M. fermentans increased IL-6, IL-8/CXCL8, MCP-1/CCL2, and Gro-alpha/CXCL1 production. M. fermentans interacted with TNF-beta to release more IL-6, CXCL8, and CXCL1 than predicted by the responses to either stimulus alone. The effects of live infection were recapitulated by exposure to M. fermentans-derived macrophage-activating lipopeptide-2 (MALP-2), a Toll-like receptor-2- and receptor-6-specific ligand. The synergistic effect of combined stimuli was more pronounced with prolonged incubations. Preexposure to TNF-beta sensitized the cells to subsequent MALP-2 challenge, but preexposure to MALP-2 did not alter the IL-6 response to TNF-beta. Exposure to M. fermentans or MALP-2 did not enhance nuclear localization, DNA binding, or transcriptional activity of NF-kappaB and did not modulate early NF-kappaB activation in response to TNF-beta. Application of specific inhibitors of various MAPKs suggested that p38 and JNK/stress-activated protein kinase were involved in early IL-6 release after exposure to TNF-beta and M. fermentans, respectively. The combined response to M. fermentans and TNF-beta, however, was uniquely sensitive to delayed application of SP-600125, suggesting that JNK/stress-activated protein kinase contributes to the amplification of IL-6 release. Thus M. fermentans interacts with stimuli such as TNF-beta to amplify lung cell production of immune-modulating cytokines. The mechanisms accounting for this interaction can now be dissected with the use of this in vitro model.
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PMID:Mycoplasma fermentans and TNF-beta interact to amplify immune-modulating cytokines in human lung fibroblasts. 1675 Dec 26

TNF-like weak inducer of apoptosis (TWEAK) is a TNF family member with pleiotropic effects on a variety of cell types, one of which is the induction of proinflammatory cytokines by synovial fibroblasts derived from rheumatoid arthritis (RA) patients. In this study, we report that the serum TWEAK level was dramatically elevated during mouse collagen-induced arthritis (CIA) and blocking TWEAK by a neutralizing mAb significantly reduced the clinical severity of CIA. Histological analyses also revealed that TWEAK inhibition diminished joint inflammation, synovial angiogenesis, as well as cartilage and bone erosion. Anti-TWEAK treatment proved efficacious when administered just before the disease onset but not during the priming phase of CIA. Consistent with this, TWEAK inhibition did not affect either cellular or humoral responses to collagen. In contrast, TWEAK inhibition significantly reduced serum levels of a panel of arthritogenic mediators, including chemokines such as MIP-1beta (CCL-4), lymphotactin (XCL-1), IFN-gamma-inducible protein 10 (IP-10) (CXCL-10), MCP-1 (CCL-2), and RANTES (CCL-5), as well as the matrix metalloprotease-9. Exploring the possible role of the TWEAK/Fn14 pathway in human RA pathogenesis, we showed that TWEAK can target human primary chondrocytes and osteoblast-like cells, in addition to synovial fibroblasts. We further demonstrated that TWEAK induced the production of matrix metalloproteases in human chondrocytes and potently inhibited chondrogenesis and osteogenesis using in vitro models. These results provide evidence for a novel cytokine pathway that contributes to joint tissue inflammation, angiogenesis, and damage, as well as may inhibit endogenous repair, suggesting that TWEAK may be a new therapeutic target for human RA.
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PMID:TWEAK is a novel arthritogenic mediator. 1688 23

The leukocyte activation marker CD69 functions as a negative regulator of the immune response, both in NK-dependent tumor rejection and in the inflammation associated with lymphocyte-dependent collagen-induced arthritis. In contrast, it has been reported that CD69-deficient mice are refractory to the neutrophil-dependent acute inflammatory response associated with anti-type II collagen antibody-induced arthritis (CAIA), suggesting a positive regulatory role for CD69 in neutrophil function during arthritis induction. To clarify this discrepancy, the CAIA response was independently analyzed in our CD69-deficient mice. In these experiments, the inflammatory response was unaffected by CD69 deficiency. Additionally, the in vivo down-regulation of CD69 expression by treatment of wild-type mice with the anti-CD69 mAb 2.2, which mimics the CD69-deficient phenotype, did not affect the course of arthritis in this model. Moreover, down-regulation of CD69 expression increased expression in arthritic joints of key inflammatory mediators, including IL-1beta, IL-6 and the chemokine MCP-1. Neutrophil accumulation in zymosan-treated air pouches and in thioglycolate-treated peritoneal cavities was also unaffected in CD69-deficient mice. In addition, CD69 expression was absent in activated neutrophils. Taken together, these results rule out a significant stimulatory role for CD69 in acute inflammatory responses mediated by neutrophils.
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PMID:The role of CD69 in acute neutrophil-mediated inflammation. 1698 25

Triptolide, a diterpenoid triepoxide from Tripterygium wilfordii Hook F (TWHF), has been proven to have potent immunosuppressive and anti-inflammatory activities. It has been clinically used to treat patients with rheumatoid arthritis (RA), in which chemokines play an important role in immune and inflammatory responses. To investigate the effect of triptolide on MCP-1, MIP-1alpha and RANTES, we used complete Freund's adjuvant to induce adjuvant-induced arthritis (AA) in rats. AA in rat is a useful experimental model of human RA. Our data show that the thickness of arthritic ankle decreases with administration of triptolide. Both mRNA and protein levels of MCP-1, MIP-1alpha and RANTES in synovial tissue of rats with AA are significantly higher than those in normal rats. mRNA levels of MIP-1alpha and RANTES increase in peripheral blood mononuclear cells of rats with AA in comparison with those in normal rats, whereas no MCP-1 mRNA can be detected. Triptolide can significantly inhibit rat AA induced over-expression of MCP-1, MIP-1alpha and RANTES at both mRNA and protein levels in a dose-dependent manner. These results may contribute to the therapeutic effects of triptolide in rheumatoid arthritis.
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PMID:Triptolide inhibits CC chemokines expressed in rat adjuvant-induced arthritis. 1705 73

TNF-like weak inducer of apoptosis (TWEAK) is a type II membrane protein belonging to the TNF family that regulates apoptotic cell death, cellular proliferation, angiogenesis, and inflammation. However, the role of TWEAK in the pathogenesis of rheumatoid arthritis (RA) remains unclear. In this study, we have investigated the effect of neutralizing anti-TWEAK mAb on the development of collagen-induced arthritis (CIA), a well-established murine model of RA. Administration of anti-TWEAK mAb significantly ameliorated paw swelling, synovial hyperplasia, and infiltration of inflammatory cells. The levels of proinflammatory chemokines such as MCP-1 and MIP-2 in serum and knee joints were reduced by this treatment. Consistently, recombinant TWEAK enhanced the proliferation of MCP-1 and MIP-2 production by synovial cells from CIA mice in vitro. Histological examination also revealed that the treatment with anti-TWEAK mAb suppressed the development of small vessels in synovial tissues. These results indicated anti-inflammatory and antiangiogenic effects of the TWEAK blockade in CIA, which may be also beneficial for the treatment of RA.
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PMID:Involvement of TNF-like weak inducer of apoptosis in the pathogenesis of collagen-induced arthritis. 1705 75

Binding of Ag-Ab immune complexes to cellular FcgammaR promotes cell activation, release of inflammatory mediators, and tissue destruction characteristic of autoimmune disease. To evaluate whether a soluble FcgammaR could block the proinflammatory effects of immune complexes, recombinant human (rh) versions of FcgammaRIA, FcgammaRIIA, and FcgammaRIIIA were prepared. Binding of rh-FcgammaRIA to IgG was of high affinity (KD=1.7x10(-10) M), whereas rh-FcgammaRIIA and rh-FcgammaRIIIA bound with low affinity (KD=0.6-1.9x10(-6) M). All rh-FcgammaR reduced immune complex precipitation, blocked complement-mediated lysis of Ab-sensitized RBC, and inhibited immune complex-mediated production of IL-6, IL-13, MCP-1, and TNF-alpha by cultured mast cells. Local or systemic delivery only of rh-FcgammaRIA, however, reduced edema and neutrophil infiltration in the cutaneous Arthus reaction in mice. 125I-labeled rh-FcgammaRIA was cleared from mouse blood with a rapid distribution phase followed by a slow elimination phase with a t1/2gamma of approximately 130 h. The highest percentage of injected radioactivity accumulated in blood approximately liver approximately carcass>kidney. s.c. dosing of rh-FcgammaRIA resulted in lower serum levels of inflammatory cytokines and prevented paw swelling and joint damage in a murine model of collagen Ab-induced arthritis. These data demonstrate that rh-FcgammaRIA is an effective inhibitor of type III hypersensitivity.
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PMID:Targeting immune complex-mediated hypersensitivity with recombinant soluble human FcgammaRIA (CD64A). 1809 60

Chemokines, including RANTES/CCL5 and MCP-1/CCL2, are highly expressed in the joints of patients with rheumatoid arthritis, and they promote leukocyte migration into the synovial tissue. This study was conducted to determine whether the inhibition of RANTES and MCP-1 therapeutically was capable of ameliorating rat of adjuvant-induced arthritis (AIA). Postonset treatment of AIA using a novel inhibitor for endogenous MCP-1 (P8A-MCP-1) improved clinical signs of arthritis and histological scores measuring joint destruction, synovial lining, macrophage infiltration, and bone erosion. Using immunohistochemistry, ELISA, real-time RT-PCR, and Western blot analysis, we defined joint inflammation, bony erosion, monocyte migration, proinflammatory cytokines, and bone markers, and p-p38 levels were reduced in rat AIA treated with P8A-MCP-1. In contrast, neither the dominant-negative inhibitor for endogenous RANTES (44AANA47-RANTES) nor the CCR1/CCR5 receptor antagonist, methionylated-RANTES, had an effect on clinical signs of arthritis when administered after disease onset. Additionally, therapy with the combination of 44AANA47-RANTES plus P8A-MCP-1 did not ameliorate AIA beyond the effect observed using P8A-MCP-1 alone. Treatment with P8A-MCP-1 reduced joint TNF-alpha, IL-1beta, and vascular endothelial growth factor levels. P8A-MCP-1 also decreased p38 MAPK activation in the joint. Our results indicate that inhibition of MCP-1 with P8A-MCP-1 after the onset of clinically detectable disease ameliorates AIA and decreases macrophage accumulation, cytokine expression, and p38 MAPK activation within the joint.
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PMID:Inhibition of monocyte chemoattractant protein-1 ameliorates rat adjuvant-induced arthritis. 1829 71

Bindarit is an indazolic derivative that is devoid of any immunosuppressive effects and has no effect on arachidonic acid metabolism. However, it has been proved to have anti-inflammatory activity in a number of experimental diseases, including pancreatitis, arthritis, and lupus nephritis. This therapeutic effect has been associated with its ability to interfere selectively with monocyte recruitment, although the underlying molecular mechanisms are unknown. Here we comprehensively examine the effect of bindarit on the chemokine system, and report that in activated monocytes and endothelial cells, it selectively inhibits the production of the monocyte chemotactic protein subfamily of CC inflammatory chemokines (MCP-1/CCL2, MCP-3/CCL7, MCP-2/CCL8). The capacity of bindarit to inhibit the production of a defined set of related CC chemokines by monocytes and endothelial cells likely underlies the anti-inflammatory activity of this agent in disease. The exploitation of the chemokine system as drug target in inflammatory disease has relied mainly on the development of receptor antagonists and blocking antibodies. Here we report on the use of inhibition of synthesis as a potentially viable and selective approach to modify the chemokine system.
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PMID:Impact of the anti-inflammatory agent bindarit on the chemokinome: selective inhibition of the monocyte chemotactic proteins. 1877 7


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