共查询到20条相似文献,搜索用时 31 毫秒
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Martinus AM van Boekel Erik R Vossenaar Frank HJ van den Hoogen Walther J van Venrooij 《Arthritis research & therapy》2001,3(2):1-7
This review focuses on the mechanisms of stress response in the synovial tissue of rheumatoid arthritis. The major stress factors, such as heat stress, shear stress, proinflammatory cytokines and oxidative stress, are discussed and reviewed, focusing on their potential to induce a stress response in the synovial tissue. Several pathways of stress signalling molecules are found to be activated in the synovial membrane of rheumatoid arthritis; of these the most important examples are heat shock proteins, mitogen-activated protein kinases, stress-activated protein kinases and molecules involved in the oxidative stress pathways. The expression of these pathways in vitro and in vivo as well as the consequences of stress signalling in the rheumatoid synovium are discussed. Stress signalling is part of a cellular response to potentially harmful stimuli and thus is essentially involved in the process of synovitis. Stress signalling pathways are therefore new and promising targets of future anti-rheumatic therapies. 相似文献
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Zheng Li Xingye Li Chao Jiang Wenwei Qian Gary Tse Matthew T.V. Chan William K.K. Wu 《Cell proliferation》2018,51(1)
Rheumatoid arthritis, a disabling autoimmune disease, is associated with altered gene expression in circulating immune cells and synovial tissues. Accumulating evidence has suggested that long non‐coding RNAs (lncRNAs), which modulate gene expression through multiple mechanisms, are important molecules involved in immune and inflammatory pathways. Importantly, many studies have reported that lncRNAs can be utilized as biomarkers for disease diagnosis and prognostication. Recently, dysregulation of lncRNAs in rheumatoid arthritis and other autoimmune diseases has been revealed. Experimental studies also confirmed their crosstalk with matrix metalloproteinases, nuclear factor‐κB signalling and T‐cell response pertinent to autoimmunity and inflammation. Circulating lncRNAs, such as HOTAIR, differentiated patients with rheumatoid arthritis from healthy subjects. Taken together, lncRNAs are good candidates as biomarkers and therapeutic targets in rheumatoid arthritis. Further investigation on in vivo delivery of these regulatory molecules and large‐cohort validation of their clinical applicability may be useful. 相似文献
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For some time synovial fibroblasts have been regarded simply as innocent synovial cells, mainly responsible for synovial homeostasis.
During the past decade, however, a body of evidence has accumulated illustrating that rheumatoid arthritis synovial fibroblasts
(RASFs) are active drivers of joint destruction in rheumatoid arthritis. Details regarding the intracellular signalling cascades
that result in long-term activation and synthesis of proinflammatory molecules and matrix-degrading enzymes by RASFs have
been analyzed. Molecular, cellular and animal studies have identified various interactions with other synovial and inflammatory
cells. This expanded knowledge of the distinct role played by RASFs in the pathophysiology of rheumatoid arthritis has moved
these fascinating cells to the fore, and work to identify targeted therapies to inhibit their joint destructive potential
is underway. 相似文献
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In vivo functions of mitogen-activated protein kinases: conclusions from knock-in and knock-out mice 总被引:4,自引:0,他引:4
Multicellular organisms achieve intercellular communication by means of signalling molecules whose effect on the target cell
is mediated by signal transduction pathways. Such pathways relay, amplify and integrate signals to elicit appropriate biological
responses. Protein kinases form crucial intermediate components of numerous signalling pathways. One group of protein kinases,
the mitogen-activated protein kinases (MAP kinases) are kinases involved in signalling pathways that respond primarily to
mitogens and stress stimuli. In vitro studies revealed that the MAP kinases are implicated in several cellular processes,
including cell division, differentiation, cell survival/apoptosis, gene expression, motility and metabolism. As such, dysfunction
of specific MAP kinases is associated with diseases such as cancer and immunological disorders. However, the genuine in vivo
functions of many MAP kinases remain elusive. Genetically modified mouse models deficient in a specific MAP kinase or expressing
a constitutive active or a dominant negative variant of a particular MAP kinase offer valuable tools for elucidating the biological
role of these protein kinases. In this review, we focus on the current status of MAP kinase knock-in and knock-out mouse models
and their phenotypes. Moreover, examples of the application of MAP kinase transgenic mice for validating therapeutic properties
of specific MAP kinase inhibitors, and for investigating the role of MAP kinase in pathogen-host interactions will be discussed. 相似文献
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Maria Sole Chimenti Paola Tucci Eleonora Candi Roberto Perricone Gerry Melino Anne E Willis 《Cell cycle (Georgetown, Tex.)》2013,12(18):3025-3036
The autoimmune process in rheumatoid arthritis depends on activation of immune cells, which utilize intracellular kinases to respond to external stimuli such as cytokines, immune complexes, and antigens. CD4+ T cells comprise a large proportion of the inflammatory cells that invade the synovial tissue and may therefore be a cell type of pathogenic importance. Both methotrexate and infliximab are effective in the treatment of inflammatory arthritis; however, the biological effects triggered by these treatments and the biochemical mechanisms underlining the cell response are still not fully understood. Thus, in this study the global metabolic changes associated with methotrexate or infliximab treatment of isolated human CD4+ T cells were examined using gas chromatography/mass spectrometry or liquid chromatography/mass spectrometry. In total 148 metabolites involved in selective pathways were found to be significantly altered. Overall, the changes observed are likely to reflect the effort of CD4+ cells to increase the production of cellular reducing power to offset the cellular stress exerted by treatment. Importantly, analysis of the global metabolic changes associated with MTX or infliximab treatment of isolated human CD4+ T cells suggested that the toxicity associated with these agents is minimal when used at clinically relevant concentrations. 相似文献
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The p38 mitogen-activated protein kinase (MAPK) cascade is an evolutionarily conserved signalling mechanism involved in processes as diverse as apoptosis, cell fate determination, immune function and stress response. Aberrant p38 signalling has been implicated in many human diseases, including heart disease, cancer, arthritis and neurodegenerative diseases. To further understand the role of p38 in these processes, we generated a Drosophila strain that is null for the D-p38a gene. Mutants are homozygous viable and show no observable developmental defects. However, flies lacking D-p38a are susceptible to some environmental stresses, including heat shock, oxidative stress and starvation. These phenotypes only partially overlap those caused by mutations in D-MEKK1 and dTAK1, suggesting that the D-p38a gene is required to mediate some, but not all, of the functions ascribed to p38 signalling. 相似文献
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Desikan R Cheung MK Bright J Henson D Hancock JT Neill SJ 《Journal of experimental botany》2004,55(395):205-212
Increased synthesis and redistribution of the phytohormone abscisic acid (ABA) in response to water deficit stress initiates an intricate network of signalling pathways in guard cells leading to stomatal closure. Despite the large number of ABA signalling intermediates that are known in guard cells, new discoveries are still being made. Recently, the reactive oxygen species hydrogen peroxide (H2O2) and the reactive nitrogen species nitric oxide (NO) have been identified as key molecules regulating ABA-induced stomatal closure in various species. As with many other physiological responses in which H2O2 and NO are involved, stomatal closure in response to ABA also appears to require the tandem synthesis and action of both these signalling molecules. Recent pharmacological and genetic data have identified NADPH oxidase as a source of H2O2, whilst nitrate reductase has been identified as a source of NO in Arabidopsis guard cells. Some signalling components positioned downstream of H2O2 and NO are calcium, protein kinases and cyclic GMP. However, the exact interaction between the various signalling components in response to H2O2 and NO in guard cells remains to be established. 相似文献
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Köller M Hayer S Redlich K Ricci R David JP Steiner G Smolen JS Wagner EF Schett G 《Arthritis research & therapy》2005,7(1):R166-R173
Tumour necrosis factor (TNF) signalling molecules are considered as promising therapeutic targets of antirheumatic therapy. Among them, mitogen-activated protein kinases are thought to be of central importance. Herein, we investigate the role in vivo of TNF-alpha signalling through c-Jun N-terminal kinase (JNK)1 in destructive arthritis. Human TNF transgenic (hTNFtg) mice, which develop inflammatory arthritis, were intercrossed with JNK1-deficient (JNK1-/-) mice. Animals (n = 35) of all four genotypes (wild-type, JNK1-/-, hTNFtg, JNK1-/-hTNFtg) were assessed for clinical and histological signs of arthritis. Clinical features of arthritis (swelling and decreased grip strength) developed equally in hTNFtg and JNK1-/-hTNFtg mice. Histological analyses revealed no differences in the quantity of synovial inflammation and bone erosions or in the cellular composition of the synovial infiltrate. Bone destruction and osteoclast formation were observed to a similar degree in hTNFtg and JNK1-/-hTNFtg animals. Moreover, cartilage damage, as indicated by proteoglycan loss in the articular cartilage, was comparable in the two strains. Intact phosphorylation of JNK and c-Jun as well as expression of JNK2 in the synovial tissue of JNK1-/-hTNFtg mice suggests that signalling through JNK2 may compensate for the deficiency in JNK1. Thus, JNK1 activation does not seem to be essential for TNF-mediated arthritis. 相似文献
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Rincón M Conze D Weiss L Diehl NL Fortner KA Yang D Flavell RA Enslen H Whitmarsh A Davis RJ 《Immunology and cell biology》2000,78(2):166-175
Mitogen-activated protein (MAP) kinases, which include the extracellular response kinases, p38 and c-Jun amino terminal kinases (JNK), play a significant role in mediating signals triggered by cytokines, growth factors and environmental stress. The JNK and p38 MAP kinases have been involved in growth, differentiation and cell death in different cell types. In the present paper, we describe how the JNK and p38 MAP kinase signalling pathways are regulated and their role during thymocyte development and the activation and differentiation of T cells in the peripheral immune system. The results from these studies demonstrate that the JNK and p38 MAP kinase signalling pathways regulate different aspects of T-cell mediated immune responses. 相似文献
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羰基毒害在糖尿病晚期并发症中的作用 总被引:2,自引:0,他引:2
动物机体组织的氧化紧张损伤和老化交联是糖尿病晚期并发症中神经病变、动脉粥样硬化、风湿性关节炎、肾病变、白内障等老化慢性疾病的共同特征.对氧化紧张到底是糖尿病晚期并发症的初始原因还是糖尿病组织衰变的次级诱因提出了探讨.结果表明糖尿病患者机体和血浆中的糖氧化产物及脂类过氧化物的增多表明病患者体内氧化紧张的加强;然而,它们中的某些产物与氧化紧张并不相关;此外,其它一些氧化紧张的直接指标,如氨基酸的氧化,在糖尿病患者的皮肤胶原中也并没有增多.因此,对于糖尿病患者中蛋白质化学修饰的现象,用活性羰基的毒化超过其系统解毒能力的观点来解释更合适.这种在氧化或非氧化反应中形成的不饱和羰基化合物在体内总是以相对恒定的浓度存在,因而在糖尿病中,由羰基毒害引起组织中糖类和脂类衍生物的增长可以被认为是生物化学动力学的一种必然结果. 相似文献
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Gringhuis SI Leow A Papendrecht-Van Der Voort EA Remans PH Breedveld FC Verweij CL 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(4):2170-2179
The T lymphocytes that reside in the synovium of the inflamed joints in patients with rheumatoid arthritis display severe hyporesponsiveness upon antigenic stimulation, which is probably due to their constant subjection to high levels of oxidative stress. Here we report that the synovial fluid T lymphocytes exert severely impaired phosphorylation of the adaptor protein linker for activation of T cells (LAT), a crucial component of the TCR-mediated signaling pathways. In healthy T lymphocytes, LAT is a membrane-bound protein and becomes phosphorylated by zeta-associated protein of 70 kDa (ZAP-70) upon TCR engagement. The molecular basis underlying the deficient phosphorylation of LAT and consequently the hyporesponsiveness of the synovial fluid T lymphocytes lies in the membrane displacement of LAT. We demonstrate that the subcellular localization of LAT is sensitive to changes in the intracellular levels of the antioxidant glutathione. The membrane anchorage of LAT, and consequently the phosphorylation of LAT and the cellular activation of the synovial fluid T lymphocytes upon TCR engagement, is restored in synovial fluid T lymphocytes after supplementation of the intracellular glutathione levels with N-acetyl-l -cysteine. These data suggest a role for the membrane displacement of LAT in the hyporesponsiveness of the synovial fluid T lymphocytes as a consequence of oxidative stress. 相似文献
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Roelofs MF Boelens WC Joosten LA Abdollahi-Roodsaz S Geurts J Wunderink LU Schreurs BW van den Berg WB Radstake TR 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(11):7021-7027
Dendritic cells (DCs) are specialized APCs that can be activated upon pathogen recognition as well as recognition of endogenous ligands, which are released during inflammation and cell stress. The recognition of exogenous and endogenous ligands depends on TLRs, which are abundantly expressed in synovial tissue from rheumatoid arthritis (RA) patients. Furthermore TLR ligands are found to be present in RA serum and synovial fluid and are significantly increased, compared with serum and synovial fluid from healthy volunteers and patients with systemic sclerosis and systemic lupus erythematosus. Identification of novel endogenous TLR ligands might contribute to the elucidation of the role of TLRs in RA and other autoimmune diseases. In this study, we investigated whether five members of the small heat shock protein (HSP) family were involved in TLR4-mediated DC activation and whether these small HSPs were present in RA synovial tissue. In vitro, monocyte-derived DCs were stimulated with recombinant alphaA crystallin, alphaB crystallin, HSP20, HSPB8, and HSP27. Using flow cytometry and multiplex cytokine assays, we showed that both alphaA crystallin and HSPB8 were able to activate DCs and that this activation was TLR4 dependent. Furthermore, Western blot and immunohistochemistry showed that HSPB8 was abundantly expressed in synovial tissue from patients with RA. With these experiments, we identified sHSP alphaA crystallin and HSPB8 as two new endogenous TLR4 ligands from which HSPB8 is abundantly expressed in RA synovial tissue. These findings suggest a role for HSPB8 during the inflammatory process in autoimmune diseases such as RA. 相似文献