共查询到20条相似文献,搜索用时 156 毫秒
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Franck Grall Xuesong Gu Lujian Tan Je‐Yoel Cho Mehmet Sait Inan Allison R. Pettit Usanee Thamrongsak Bob K. Choy Cathy Manning Yasmin Akbarali Luiz Zerbini Susan Rudders Steven R. Goldring Ellen M. Gravallese Peter Oettgen Mary B. Goldring Towia A. Libermann 《Arthritis \u0026amp; Rheumatology》2003,48(5):1249-1260
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Matilde Todaro Monica Zerilli Giovanni Triolo Flora Iovino Mariella Patti Antonina Accardo‐Palumbo Francesca di Gaudio Maria Caterina Turco Antonello Petrella Ruggero de Maria Giorgio Stassi 《Arthritis \u0026amp; Rheumatology》2005,52(7):2179-2191
Objective
To determine whether prolongation of the inflammatory reaction in patients with Behçet's disease (BD) is related to apoptosis resistance and is associated with the up‐regulation of antiapoptotic factors.Methods
The percentage of cell death was evaluated by flow cytometry in peripheral blood mononuclear cells from 35 patients with BD and 30 healthy volunteers. The expression levels of antiapoptotic factors and NF‐κB regulatory proteins were measured using Western blotting and immunohistochemical analyses. To down‐regulate NF‐κB nuclear translocation, BD T lymphocytes were exposed in vitro to thalidomide and subjected to transfection with NF‐κB small interfering RNA.Results
Although CD95 is highly expressed in BD T cells, the absence of sensitivity to CD95‐induced apoptosis observed may be attributable to the inhibitory action of antiapoptotic genes. Immunoblot analysis for major antiapoptotic proteins showed considerable up‐regulation of the short form of cellular FLIP (cFLIP) and Bcl‐xL in BD activated T cells, while levels of Bcl‐2, caspase 3, and caspase 8 in activated T cells from patients with BD were comparable with those in activated T cells from normal donors. Moreover, expression of IKK and IκB was up‐regulated, whereas NF‐κB translocated to the nucleus in BD T cells, suggesting that NF‐κB activation may modulate the expression of antiapoptotic genes. Interestingly, thalidomide and NF‐κB small interfering RNA down‐regulated cFLIP and Bcl‐xL expression levels and sensitized BD activated T cells to CD95‐induced apoptosis.Conclusion
Taken together, these results indicate that NF‐κB contributes to the regulation of the apoptosis‐related factors and death receptors leading to apoptosis resistance in BD T cell subsets. Our results suggest that NF‐κB plays a crucial role in the pathogenesis of BD, and that its pharmacologic control could represent a key strategy in modulating specific immune‐mediated disease.12.
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Michelle Trenkmann Matthias Brock Renate E. Gay Beat A. Michel Steffen Gay Lars C. Huber 《Arthritis \u0026amp; Rheumatology》2013,65(4):916-927
Objective
To elucidate whether the microRNA (miRNA) cluster miR‐17–92 contributes to the activated phenotype of rheumatoid arthritis synovial fibroblasts (RASFs).Methods
RASFs were stimulated with tumor necrosis factor α (TNFα), and the expression and regulation of the miR‐17–92 cluster were studied using real‐time quantitative PCR (PCR) and promoter activity assays. RASFs were transfected with single precursor molecules of miRNAs from miR‐17–92 and the expression of matrix‐degrading enzymes and cytokines was measured by quantitative PCR and enzyme‐linked immunosorbent assay. Potential miRNA targets were identified by computational prediction and were validated using reporter gene assays and Western blotting. The activity of NF‐κB signaling was determined by reporter gene assays.Results
We found that TNFα induces the expression of miR‐17–92 in RASFs in an NF‐κB–dependent manner. Transfection of RASFs with precursor molecules of single members of miR‐17–92 revealed significantly increased expression levels of matrix‐degrading enzymes, proinflammatory cytokines, and chemokines in precursor miR‐18a (pre‐miR‐18a)–transfected RASFs. Using reporter gene assays, we identified the NF‐κB pathway inhibitor TNFα‐induced protein 3 as a new target of miR‐18a. In addition, pre‐miR‐18a–transfected RASFs showed stronger activation of NF‐κB signaling, both constitutively and in response to TNFα stimulation.Conclusion
Our data suggest that the miR‐17–92–derived miR‐18a contributes to cartilage destruction and chronic inflammation in the joint through a positive feedback loop in NF‐κB signaling, with concomitant up‐regulation of matrix‐degrading enzymes and mediators of inflammation in RASFs.15.
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Nasim Yousaf David J. Gould Ebun Aganna Linda Hammond Rita M. Mirakian Mark D. Turner Graham A. Hitman Michael F. McDermott Yuti Chernajovsky 《Arthritis \u0026amp; Rheumatology》2005,52(9):2906-2916
Objective
To investigate the molecular consequences of expressing mutated forms of tumor necrosis factor receptor I (TNFRI) as found in patients with TNFR‐associated periodic syndrome (TRAPS).Methods
We cloned and expressed full‐length wild‐type (WT) and T50K and P46L variants of TNFRI using a new tightly regulated doxycycline‐dependent expression system. This system enabled the study of molecular interactions between these receptors at both physiologic and pathophysiologic levels of expression.Results
We used chemical crosslinking on the cell surface to show that WT and mutant forms of TNFRI, derived from TRAPS patients, interact in the absence of TNF ligand. Doxycycline‐controlled up‐regulation of one TNFRI allele, either WT or mutant, caused down‐regulation of the other allele, indicating dynamic control of cell surface assembly. We also demonstrated that increased expression of mutant TNFRI (T50K) was associated with a parallel increase in NF‐κB p65 (RelA) subunit activation, which did not occur with increased expression of WT TNFRI.Conclusion
The T50K TRAPS‐related variant is capable of sustaining inappropriate NF‐κB activation, resulting in persistent autoinflammation in target organs such as skin, synovial membrane, and the central nervous system. We conclude that some of the inflammatory processes seen in TRAPS do not involve direct interaction of TNF with its receptors, but that other proinflammatory mechanisms capable of up‐regulating TNFRI expression may cause cellular activation through the NF‐κB signaling pathway.17.
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Chary Lpez‐Pedrera Paula Buendía Maria Jos Cuadrado Emilio Siendones Maria Angeles Aguirre Nuria Barbarroja Cristina Montiel‐Duarte Antonio Torres Munther Khamashta Francisco Velasco 《Arthritis \u0026amp; Rheumatology》2006,54(1):301-311