Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclosporine A (CSA) has various biological effects on T cells, including inhibition of interleukin (IL)-15-induced IL-17 production in CD4+ T cells from patients with rheumatoid arthritis (RA). However, the mechanism underlying this effect is not fully understood. Here, we tried to investigate the mechanism of CSA to inhibit IL-17 production induced by IL-15 in CD4+ T cells. Synovial fluid and serum levels of IL-15 and IL-17 were determined by ELISA. CD4+ T cells from RA patients were treated with IL-15 in the presence of CSA or several signal inhibitors. The concentration of IL-17 in culture supernatants was measured by ELISA and IL-17 mRNA expression was determined by RT-PCR. NF-kappaB binding activity for IL-17 transcription was assessed by electrophoretic mobility shift assay. IL-15 induced IL-17 production by CD4+ T cells in dose- and time-dependent manner. IL-15-stimulated IL-17 production and mRNA expression were inhibited by CSA in CD4+ T cells. Moreover PI3K/Akt inhibitor, NF-kappaB inhibitor, and FK506 significantly inhibited IL-15-induced IL-17 production in CD4+ T cells. Inhibition studies revealed the requirement of PI3K/Akt and NF-kappaB signal pathway for IL-15-induced IL-17 production. CSA down-regulated the phosphorylation of Akt and IkappaB. CSA inhibited binding of NF-kappaB to IL-17 promoter. The inhibitory effect of CSA on IL-15 induced IL-17 production partially depended on the increase in IL-10, since neutralizing anti-IL-10 antibodies were able to partially reverse this inhibition. CSA inhibits IL-17 production by CD4+ T cells and this effect is mediated by IL-15-activated NF-kappaB pathway in CD4+ T cells, which is possible mechanism of CSA in treating RA as NF-kappaB targeting strategy.
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PMID:Cyclosporine A inhibits IL-15-induced IL-17 production in CD4+ T cells via down-regulation of PI3K/Akt and NF-kappaB. 1716 67

The transcription factor STAT4 mediates signals of various proinflammatory cytokines, such as IL-12, IL-15, and IL-23, that initiate and stabilize Th1 cytokine production. Although Th1 cytokine production has been suggested to play a major pathogenic role in rheumatoid arthritis, the role of STAT4 in this disease is poorly understood. In this study, we demonstrate a key functional role of STAT4 in murine collagen-induced arthritis (CIA). In initial studies we found that STAT4 expression is strongly induced in CD4(+) T cells and to a lesser extent in CD11b(+) APCs during CIA. To analyze the role of STAT4 for arthritis manifestation, we next investigated the outcome of interfering with STAT4 gene expression in CIA by using STAT4-deficient mice. Interestingly, STAT4-deficient mice developed significantly less severe arthritis than wild-type control mice and the T cells from such mice produced less IL-6, TNF, and IL-17. In addition, the targeting of STAT4 expression by a specific antisense phosphorothioate oligonucleotide directed at the translation start site suppressed STAT4 levels and signs of CIA even when applied during the onset of disease manifestation. These data suggest a key regulatory role of STAT4 in the pathogenesis and manifestation of murine collagen-induced arthritis. Furthermore, the targeting of STAT4 emerges as a novel approach to therapy for chronic arthritis.
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PMID:Targeting of the transcription factor STAT4 by antisense phosphorothioate oligonucleotides suppresses collagen-induced arthritis. 1733 37

Advances in our understanding of the pathogenesis of rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus have led to the emergence of immunoglobulin-based therapy as a major therapeutic force. Numerous monoclonal antibodies that target proinflammatory cytokines or their receptors (e.g. infliximab, adalimumab, tocilizumab, belimumab, HuMax-IL-15), and cell-surface or co-stimulatory molecules (e.g. rituximab) are either in clinical development or have been approved for clinical use. These antibodies are safe and effective in the long-term therapy of many rheumatic diseases. In addition, polyclonal immunoglobulins (intravenous immunoglobulin) obtained from pooled plasma from healthy blood donors are an effective therapeutic approach in certain rheumatic diseases. The mechanisms of action of monoclonal antibodies and intravenous immunoglobulin include cytolysis of target cells through complement or antibody-dependent cell-mediated cytotoxicity, induction of apoptosis of target cells, blockade of co-stimulatory molecules, and neutralization of pathogenic antibodies and soluble factors such as cytokines and their receptors, which ultimately lead to amelioration of the inflammatory process. The success of currently available therapeutic immunoglobulins has led to considerable interest in the identification of novel molecular therapeutic targets in rheumatic diseases.
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PMID:Monoclonal antibody and intravenous immunoglobulin therapy for rheumatic diseases: rationale and mechanisms of action. 1747 Dec 45

Advances in molecular biology and the clinical success of strategies that target tumor necrosis factor (TNF) have led to further research into the pathophysiology of human rheumatoid arthritis. Several novel therapeutic targets have emerged from these efforts, including not only molecules that regulate TNF (e.g. TNF-alpha converting enzyme), the complex cytokine network (e.g. interleukin [IL]-6, IL-15, IL-17) and several adipokines, but also targets that originate from cellular and subcellular components of the disease. Strategies that aim at cellular targets include antibodies to CD20 or BLyS (also known as TNF ligand family member 13b), which deplete or inhibit B cells, as well as approaches that interfere with membrane-derived microparticles. Components of subcellular pathways, which are predominantly upstream of the central regulator of transcription nuclear factor kappaB, have also been studied. Of these, strategies that target mitogen-activated protein kinases have a leading role and are on the verge of clinical use; approaches that target specific molecules such as Janus kinases, signal transducer and activator of transcription proteins, and suppressor of cytokine signaling proteins also seem to show promise and might have a clinical application in the future.
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PMID:Emerging targets of biologic therapies for rheumatoid arthritis. 1753 65

There have recently been fewer publications written in Japanese describing inflammatory cytokines in rheumatoid arthritis (RA) other than tumor necrosis factor and interleukin (IL) -6. Interleukins such as IL-1 and IL-15 are thought to play an important role, at least in part, in pathogenesis of RA. In this review, the two interleukins above were mentioned from mainly RA point of view, respectively. Monoclonal antibody to each cytokine might be brought to the clinic in the future.
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PMID:[Antibody to IL-1 or IL-15]. 1764 36

Proinflammatory cytokines as well as CD4(+) T cells play critical roles in the pathogenesis of rheumatoid arthritis (RA). Recently, an increase of CD57(+) or CD28(-)CD4(+) T cells was demonstrated in RA, although the mechanism of the increase of these T cells is unclear. In this study, we first examined the relationship between CD57(+)CD4(+) T cells and CD28(-)CD4(+) T cells and found CD57(+)CD28(-)CD4(+) T cells, but neither CD57(+)CD28(+) nor CD57(-)CD28(+) cells, expanded in the peripheral blood of active RA. In vitro experiments revealed that CD57(+)CD28(-)CD4(+) T cells selectively expanded in response to IL-15. Furthermore IL-15-stimulated CD57(+)CD28(-)CD4(+) T cells induced TNF-alpha production from monocytes. These results suggest that CD57(+)CD28(-)CD4(+) T cells are involved in the pathogenesis of RA by responding to IL-15.
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PMID:Interleukin-15 selectively expands CD57+ CD28- CD4+ T cells, which are increased in active rheumatoid arthritis. 1764 42

Receptor activator of nuclear factor XB ligand (RANKL) belongs to the TNF superfamily of cytokines. It plays a key role in osteoclastogenesis, activation, and survival of osteoclasts. The differentiation of macrophage/monocyte-like cells into osteoclasts critically depends on the binding of monocyte-colony stimulating factor (M-CSF) and RANKL by their respective plasma-membrane receptors, c-Fms and RANK. Osteoprotegerin (OPG), a soluble protein of the TNF receptor superfamily that is synthesized mainly by osteoblasts, is a decoy receptor that binds RANKL. In this way OPG competes with RANK what results in the inhibition of osteoclastogenesis and bone resorption. It has been shown that the RANKL/OPG ratio may determine the delicate balance between bone resorption and synthesis. Under normal conditions RANKL is mainly produced by osteoblasts and bone marrow stromal cells. However, in many pathological conditions such as rheumatoid arthritis (RA) and neoplastic osteolysis RANKL is also produced by T and B lymphocytes, macrophages/ monocytes, fibroblasts, synoviocytes, and megakaryocytes. In RA osteolysis is promoted not only by M-CSF and RANKL, but also by other cytokines (TNF, IL-1beta, IL-6, IL-7, IL-11, IL-15, IL-17, IL-18), hormones (PTH, PTH-rP, corticosteroids), and prostaglandin E2. On the contrary, OPG, interferon gamma, IL-4, TGF-beta, bifosfonians, and estrogens inhibit RA-associated osteoclastogenesis. Recently, therapeutics for pathological bone destruction targeting RANKL pathways have been used for the treatment of postmenopausal osteoporosis.
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PMID:[Role of tumor necrosis factor family ligands in the pathogenesis of rheumatoid arthritis--new therapeutical opportunities]. 1768 31

IL-15 is thought to be involved in the pathogenesis of rheumatoid arthritis (RA). We found that IL-15 plays an important role in the development of murine collagen-induced arthritis (CIA). The incidence and severity of CIA were slightly decreased in IL-15 KO mice but were increased in IL-15 Tg mice compared with wild-type (WT) mice. The levels of type II collagen (CII)-specific IL-17 production were significantly increased in IL-15 Tg mice compared with WT mice with CIA. Expression of IL-23R was up-regulated in CD4(+) T cells in IL-15 Tg mice but down-regulated in IL-15 KO mice compared with WT mice. In correlation with the expression levels of IL-23R, IL-17 production by CD4(+) T cells in response to exogenous IL-23 was increased in IL-15 Tg mice compared with WT mice. Furthermore, exogenous IL-15 synergized with IL-23 to induce CII-specific IL-17 production by CD4(+) T cells in vitro. Taken together, these results indicate that IL-15 plays an important role in the progression of CIA through increasing antigen-specific IL-17 production by CD4(+) T cells.
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PMID:IL-15 exacerbates collagen-induced arthritis with an enhanced CD4+ T cell response to produce IL-17. 1782 84

Cytokine and chemokine receptors play a key role in inflammation caused by rheumatoid arthritis (RA). Two isoforms of human CC chemokine receptor R2 (CCR2), the receptor of monocyte chemoattractant protein 1 (MCP-1), have been identified but their relative expression in fibroblast-like synoviocytes (FLS) and their contribution to inflammatory responses mediated by MCP-1 or inflammatory cytokines in patients with RA remain uncertain. We examined the pattern of expression of two CCR2 isoforms upon stimulation by proinflammatory cytokines and CD40 ligation. FLS were prepared from the synovial tissues of RA patients and cultured in the presence of MCP-1, soluble CD40 ligand (sCD40L), TGF-beta, IL-1beta, IL-18, IL-15, and LPS. CCR2A and CCR2B expression was examined by immunohistochemistry, RT-PCR and western blot analysis. IL-15, TNF-alpha and MCP-1 production was determined by ELISA. Immunohistochemistry showed that CCR2A is highly expressed in RA synovium compared with OA synovium. Transcripts of both CCR2A and CCR2B were detected in FLS. Exogenous MCP-1, CD40L, TGF-beta, and IL-15 significantly increased the expression of CCR2A but not CCR2B. Exposure of FLS to sCD40L caused strong upregulation of CCR2A but not of CCR2B protein expression. MCP-1 increased the proliferation of FLS and the production of IL-15, TNF-alpha, and IL-18. Because CCR2A is the main target of regulation by cytokines and CD40 ligation, the relatively higher expression of CCR2A on the cell surface suggests that this isoform of MCP-1 receptor functions as the principal mediator of inflammatory signals in RA FLS.
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PMID:Expression of CCR2A, an isoform of MCP-1 receptor, is increased by MCP-1, CD40 ligand and TGF-beta in fibroblast like synoviocytes of patients with RA. 1793 38

We have investigated the mechanisms underlying IL-15-induced neutrophil migration into inflamed tissues. IL-15 induced neutrophil migration to the peritoneal cavity in mice in a time- and dose-dependent manner. The cell migration was not induced in IL-18-/-, MIP-1alpha (CCL3)-/-, TNFR1-/- or 5-LOX-/- mice but was normal in IFN-gamma-/- mice. IL-15-induced neutrophil migration was inhibited by anti-MIP-2 (CXCL2) antibody or MK886 (leukotriene synthesis inhibitor). IL-18-induced neutrophil migration was also dependent on TNFR1, MIP-1alpha, MIP-2 and leukotriene. Consistent with this observation, IL-15 induced IL-18 production, and IL-15 or IL-18 injection induced the production of MIP-2, MIP-1alpha, TNF-alpha and LTB4. In an antigen-specific inflammation model, ovalbumin (OVA)-induced neutrophil migration was completely inhibited by soluble IL-15Ralpha (sIL-15Ralpha) or anti-MIP-2 antibody. Furthermore, cell migration was absent in IL-18-/-, MIP-1alpha-/-, TNFR1-/-, or 5-LOX-/- mice. OVA challenge induced the release of MIP-2, MIP-1alpha, TNF-alpha and LTB4 in the peritoneal cavity in an IL-15- and IL-18-dependent manner. We also found that neutrophils from the peripheral blood and synovial fluid of patients with rheumatoid arthritis produced substantial amounts of IL-18 and LTB4 following activation by IL-15. Together, these results demonstrate that IL-15 plays an important role in antigen-induced neutrophil migration during inflammation, triggering a sequential OVA, IL-15, IL-18, MIP-2, MIP-1alpha, TNF-alpha, LTB4 and neutrophil migration signaling cascade.
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PMID:IL-15 mediates antigen-induced neutrophil migration by triggering IL-18 production. 1797 56


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