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)

Ceramide has been proposed as a second messenger molecule implicated in a variety of biological processes, including apoptosis. Recently, it has been reported that tumor necrosis factor-alpha (TNF-alpha) activates the release of ceramide and that ceramide acts as a mediator for the TNF-alpha-induced stimulation of the binding affinity of nuclear factor-KB (NF-KB), a ubiquitous transcription factor of particular importance in immune and inflammatory responses. In this study we demonstrate that dexamethasone, which reduces the production of ceramide, significantly inhibits TNF-alpha-induced activation of NF-KB, c-Jun N-terminal kinase, also known as stress-activating protein kinase, caspase-3-like cysteine protease, redistribution of cytochrome c, and apoptosis in MC3T3E1 osteoblasts. Compared with TNF-alpha-induced JNK activation, ceramide elicits a more rapid activation of JNK within 30 min. C2-ceramide activates NF-KB and caspase-3 like protease to the same degree and with kinetics similar to those of TNF-alpha. This study provides evidence that the release of ceramide may be required as a second messenger in TNF-alpha-induced apoptosis. These results also suggest a regulatory role for dexamethasone in TNF-alpha-induced apoptosis via inhibition of ceramide release. Therefore, our in vitro results suggest that therapies targeted at the inhibition of ceramide release may abrogate inflammatory processes in TNF-alpha-related diseases, including rheumatoid arthritis and periodontitis.
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PMID:Dexamethasone suppresses tumor necrosis factor-alpha-induced apoptosis in osteoblasts: possible role for ceramide. 1091 78

As in rheumatoid arthritis (RA), it was demonstrated recently that bacterial fragments of DNA or rRNA are present in the joint and therefore could play a role in inducing or perpetuating the disease, this work was initiated to define mechanisms that account for the stimulatory activities of the oral streptococcal modulin, protein I/II, on fibroblast-like synoviocytes (FLSs) from RA patients. FLSs from RA patients were stimulated with protein I/II, and expression of interleukin (IL)-6 and IL-8 mRNA was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Immunoblotting by antibodies specific for activated forms of MAPKs and electrophoretic mobility shift assays (EMSAs) were performed to study downstream signalling, which allowed the synthesis of IL-6 and IL-8. We reported that protein I/II interactions with FLSs from RA patients trigger the synthesis and release of IL-6 and IL-8. We also demonstrated that protein I/II enhances the phosphorylation of ERK 1/2, p38 and JNKs and that ERK 1/2 and JNK MAPKs seem to play a more important role than p38 in protein I/II-mediated synthesis of IL-6 and IL-8. Our experiments also indicated that stimulation of FLSs with protein I/II induces nuclear translocation of NF-kappaB, AP-1-binding activity and that NF-kappaB plays a major role in IL-6 and IL-8 secretion from activated cells.
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PMID:NF-kappaB and the MAP kinases/AP-1 pathways are both involved in interleukin-6 and interleukin-8 expression in fibroblast-like synoviocytes stimulated by protein I/II, a modulin from oral streptococci. 1158 Jul 55

Rheumatoid arthritis is a prevalent example of an inflammatory angiogenic disease, which is mediated by pro-inflammatory and pro-angiogenic cytokines such as tumor necrosis factor (TNF). To evaluate the effect of the potent anti-angiogenic factor endostatin on TNF-induced inflammatory arthritis, we injected an endostatin-expressing lentiviral vector directly into the joints of human TNF-transgenic mice before the onset of disease. Histological analysis of the injected joints 8 weeks later revealed that endostatin reduced blood vessel density within the synovial tissues and an overall mean arthritis index. In vitro and in vivo examination of the potential mechanism by which endostatin inhibited the arthritis revealed that endostatin blocks TNF-induced activation of JNK and JNK-dependent pro-angiogenic gene expression. These data suggest a novel mechanism by which endostatin inhibits angiogenesis, and demonstrates the potential utility of anti-angiogenic gene therapy for treatment of inflammatory arthritis.
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PMID:Endostatin gene transfer inhibits joint angiogenesis and pannus formation in inflammatory arthritis. 1199 45

Activation of CD4(+) T cells is governed by interplay between stimulatory and inhibitory receptors; predominance of stimulatory signals favors autoimmune reactions. In patients with rheumatoid arthritis, expression of the critical costimulatory molecule, CD28, is frequently lost. Instead, CD4(+)CD28(null) T cells express killer immunoglobulin-like receptors (KIRs) with a preferential expression of the stimulatory receptor, CD158j. The frequency of CD4(+)CD28(null) T cells in rheumatoid arthritis (RA) correlates with the risk for more severe disease. Moreover, the KIR2DS2 gene, which encodes for CD158j, is a genetic risk factor for rheumatoid vasculitis. CD158j signals through the adaptor molecule, KARAP/DAP12, to positively regulate cytotoxic activity in NK cells. However, the majority of CD4(+)CD28(null) T cell clones lacked the expression of KARAP/DAP12. Despite the absence of KARAP/DAP12, CD158j was functional and augmented interferon-gamma production after T cell receptor stimulation. Cross-linking of CD158j resulted in selective phosphorylation of c-Jun NH(2)-terminal protein kinase (JNK) and its upstream kinase, MKK4 that led to the expression of ATF-2 and c-Jun, all in the absence of extracellular signal-regulated kinase (ERK)1/2 phosphorylation. Mutation of the lysine residue within the transmembrane domain of CD158j abolished JNK activation, suggesting that an alternate adaptor molecule was being used. CD4(+)CD28(null) T cells expressed DAP10 and inhibition of phosphatidylinositol 3-kinase, which acts downstream of DAP10, inhibited JNK activation; however, no interaction of DAP10 with CD158j could be detected. Our data suggest that CD158j in T cells functions as a costimulatory molecule through the JNK pathway independent of KARAP/DAP12 and DAP10. Costimulation by CD158j may contribute to the autoreactivity of CD4(+)CD28(null) T cells in RA.
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PMID:Selective activation of the c-Jun NH2-terminal protein kinase signaling pathway by stimulatory KIR in the absence of KARAP/DAP12 in CD4+ T cells. 1259 2

Tumor necrosis factor (TNF) is a potent inflammatory cytokine involved in many pathophysiological conditions including rheumatoid arthritis and Crohn's disease. Despite recent evidence regarding signal transduction via TNF receptor and its biological actions, the mechanism of TNF release remains poorly understood. To clarify how production and release of TNF are regulated, we focused on mast cells and microglia which are involved in allergic inflammation and brain damage or recovery, respectively. In RBL-2H3 mast cells, anti-allergic drugs including azelastine inhibited the release of TNF more potently than degranulation in response to antigen or ionomycin. It was also demonstrated that TNF releasing steps are regulated via the PKC alpha-dependent pathway. Furthermore, Rho GTPases, possibly Rac, were shown to be involved in antigen-induced TNF transcription through activating PKC beta I. In cultured rat brain microglia, we found that extracellular ATP triggers the release of TNF via the P2X7 receptor. ERK and JNK are also involved in ATP-induced TNF transcription, while p38 regulates the transport of TNF mRNA from the nucleus to the cytosol. Additionally, JNK and p38, but not ERK, are activated via the P2X7 receptor. A better understanding of the specific pathways that regulate TNF release for each effector cell may offer further possible therapeutic targets for inflammatory diseases.
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PMID:[Mechanism of production and release of tumor necrosis factor implicated in inflammatory diseases]. 1267 50

TNFalpha is a crucial cytokine in the establishment and maintenance of inflammation in multiple autoimmune diseases. With the introduction of infliximab and etanercept, two injectable biologic TNFalpha blocking drugs are now available. Both are effective in the treatment of rheumatoid arthritis, reducing clinical inflammation and damage to bones. In addition, infliximab is FDA-approved for the treatment of Crohn's disease. More recent controlled trials have shown effectiveness for TNFalpha blockers in psoriasis, psoriatic arthritis, and ankylosing spondylitis. Further trials are underway in diverse inflammatory conditions including including uveitis, sarcoidosis, Behcet's syndrome, and graft versus host disease. Although the safety profile has been generally excellent, the rare development of reactivation tuberculosis, anti double-stranded DNA antibodies, or a demyelination syndrome point out the need for further close follow-up of treated patients. New formulations of recombinant anti-TNFalpha biologics undergoing clinical trials use modifications to reduce antigenicity, increase the half-life, and maintain or extend the efficacy of these agents. Future development of TNFalpha antagonists is turning to small molecule inhibitors. The inhibition of the TNFalpha signaling cascade is under study using blockers of the p38, JNK, and ERK kinases, and by antagonists of transcription factor NF-kappaB activation. The goal of this approach is to develop compounds that are orally available, have increased selectivity compared to generalized blockade of TNFalpha, yet are therapeutically useful for a range of chronic inflammatory diseases.
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PMID:TNFalpha as therapeutic target: new drugs, more applications. 1456 Nov 84

Tumor necrosis factor alpha (TNFalpha) inhibits matrix synthesis by chondrocytes in rheumatoid arthritis and osteoarthritis; however, the underlying signaling pathways are poorly characterized. This study investigated the TNFalpha-activated pathways regulating expression of two key components of the cartilage matrix-link protein and type II collagen. In rat articular chondrocytes, TNFalpha decreased link protein and type II collagen mRNA to undetectable levels within 48 h. Levels of link protein mRNA recovered more readily than type II collagen mRNA following removal of the cytokine. TNFalpha-mediated reduction in mRNA of both matrix molecules occurred at the level of transcription and, for link protein, mRNA stability. Turnover of type II collagen and link protein mRNA was dependent on new protein synthesis. In both prechondrocytes and articular chondrocytes, TNFalpha induced concentration-dependent activation of MEK1/2 and NF-kappaB, but not p38 or JNK. Sustained activation of NF-kappaB was observed for up to 72 h following continuous or transient exposure to TNFalpha. Using pharmacological and molecular approaches, the MEK1/2 and NF-kappaB pathways were found to mediate inhibition of type II collagen and link protein gene expression by TNFalpha. Both prechondrocytes and articular chondrocytes are targets of TNFalpha. This study identifies pathways through which TNFalpha perturbs the synthesis and organization of articular cartilage matrix during inflammation.
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PMID:TNFalpha suppresses link protein and type II collagen expression in chondrocytes: Role of MEK1/2 and NF-kappaB signaling pathways. 1456 65

Unfettered hyaluronan (HA) production is a hallmark of rheumatoid arthritis. The discovery of three genes encoding hyaluronan synthases (HASs) allows for the investigation of the signaling pathways leading to the activation of these genes. Our objective is to further understanding of the regulation of these genes as well as to find ways to prevent undesired gene activation. Human fibroblast-like synoviocytes were used in these experiments. mRNA levels of HAS were monitored by reverse transcriptase-PCR. A series of specific kinase inhibitors were used to investigate intracellular pathways leading to the up-regulation of HAS1. Our experiments, testing a series of stimuli including tumor necrosis factor alpha (TNFalpha), demonstrate that TGF-beta is the most potent stimulus for HAS1 transcription. TGF-beta activates HAS1 in a dose-dependent manner with a maximum effect at a concentration of 0.5-1 ng/ml. TGF-beta-induced HAS1 mRNA can be detected within 60 min and reaches maximal levels at 6 h. Furthermore, TGF-beta treatment leads to an increase in synthase activity as determined by HA ELISA and by in vitro HA synthase assays. In contrast to the activatory effect on HAS1, TGF-beta dose-dependently suppresses HAS3 mRNA. As to the mode of action of TGF-beta-induced HAS1 mRNA activation, our experiments reveal that blocking p38 MAPK inhibited the TGF-beta effect by 90%, blocking the MEK pathway led to an inhibition by 40%, and blocking the JNK pathway had no effect. The presented data might contribute to a better understanding of the role of TGF-beta and of HA in the pathology of diseases.
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PMID:Differential effect of transforming growth factor beta (TGF-beta) on the genes encoding hyaluronan synthases and utilization of the p38 MAPK pathway in TGF-beta-induced hyaluronan synthase 1 activation. 1467 2

The cyclooxygenase 2 (COX-2) inhibitor celecoxib (also called celebrex), approved for the treatment of colon carcinogenesis, rheumatoid arthritis, and other inflammatory diseases, has been shown to induce apoptosis and inhibit angiogenesis. Because NF-kappa B plays a major role in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation, we postulated that celecoxib modulates NF-kappa B. In the present study, we investigated the effect of this drug on the activation of NF-kappa B by a wide variety of agents. We found that celecoxib suppressed NF-kappa B activation induced by various carcinogens, including TNF, phorbol ester, okadaic acid, LPS, and IL-1 beta. Celecoxib inhibited TNF-induced I kappa B alpha kinase activation, leading to suppression of I kappa B alpha phosphorylation and degradation. Celecoxib suppressed both inducible and constitutive NF-kappa B without cell type specificity. Celecoxib also suppressed p65 phosphorylation and nuclear translocation. Akt activation, which is required for TNF-induced NF-kappa B activation, was also suppressed by this drug. Celecoxib also inhibited the TNF-induced interaction of Akt with I kappa B alpha kinase (IKK). Celecoxib abrogated the NF-kappa B-dependent reporter gene expression activated by TNF, TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor 2, NF-kappa B-inducing kinase, and IKK, but not that activated by p65. The COX-2 promoter, which is regulated by NF-kappa B, was also inhibited by celecoxib, and this inhibition correlated with suppression of TNF-induced COX-2 expression. Besides NF-kappa B, celecoxib also suppressed TNF-induced JNK, p38 MAPK, and ERK activation. Thus, overall, our results indicate that celecoxib inhibits NF-kappa B activation through inhibition of IKK and Akt activation, leading to down-regulation of synthesis of COX-2 and other genes needed for inflammation, proliferation, and carcinogenesis.
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PMID:Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-kappa B activation through inhibition of activation of I kappa B alpha kinase and Akt in human non-small cell lung carcinoma: correlation with suppression of COX-2 synthesis. 1526 36

Stimulatory killer Ig-like receptors (KIRs) are expressed by various lymphocytes, including NK cells and subsets of T cells. In NK cells, KIRs associate with the adapter molecule KARAP/DAP12, which confers the ability to function as an independent activation unit. The function of KIRs and killer cell activating receptor-associated protein (KARAP)/DAP12 in T cells is unclear. By flow cytometry, we demonstrated that CD4+CD28null T cells heterogeneously express KIRs and/or KARAP/DAP12. In clones that lacked expression of KARAP/DAP12, the stimulatory KIR KIR2DS2 signaled through the JNK pathway, but did not activate the ERK pathway. However, in the presence of KARAP/DAP12, stimulation through KIR2DS2 led to phosphorylation of both JNK and ERK. Transfection experiments confirmed that KIR2DS2-mediated ERK phosphorylation was dependent on KARAP/DAP12. The differential signaling of KIR2DS2 through association with alternative adapter molecules resulted in differential regulation of cellular activity. In clones that lacked expression of KARAP/DAP12, stimulation of KIR2DS2 did not induce cytotoxicity. However, KIR2DS2 did augment suboptimal TCR stimulation, leading to enhanced IFN-gamma production. In clones that expressed KARAP/DAP12, KIR2DS2 directly activated both cytotoxicity and IFN-gamma production without the need for TCR-derived signals. The function of stimulatory KIRs in T cells is determined by the expression of the appropriate adapter molecule. Expression of KARAP/DAP12 is sufficient to convert a costimulatory KIR into a stimulatory molecule. These differing functions mediated by alternative signaling pathways have implications for the pathogenesis of diseases such as rheumatoid arthritis and acute coronary syndromes, in which aberrant expression of KIRs on T cells is frequently observed.
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PMID:Stimulatory killer Ig-like receptors modulate T cell activation through DAP12-dependent and DAP12-independent mechanisms. 1535 18


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