共查询到20条相似文献,搜索用时 46 毫秒
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TNF-R1 signaling: a beautiful pathway 总被引:1,自引:0,他引:1
Tumor necrosis factor (TNF) is a major mediator of apoptosis as well as inflammation and immunity, and it has been implicated in the pathogenesis of a wide spectrum of human diseases, including sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases. The interaction of TNF with TNF receptor-1 (TNF-R1) activates several signal transduction pathways. A common feature of each pathway is the TNF-induced formation of a multiprotein signaling complex at the cell membrane. Over the past decade, many of the components and mechanisms of these signaling pathways have been elucidated. We provide an overview of current knowledge of TNF signaling and introduce an STKE Connections Map that depicts a canonical view of this process. 相似文献
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细胞凋亡和细胞坏死是细胞死亡的两种形式,前者属于生理性的平衡机制,后者则是由于致病因子作用下发生的病理过程。免疫系统抑制与细胞凋亡有关,在免疫系统中存在两种细胞程序性死亡,一种是在无生长因子时,Bcl-2基因调控的程序化死亡;另一种是细胞毒介导的靶细胞的程序化死亡。细胞凋亡是动物机体对病毒侵入的一种防御机制之一,当细胞凋亡和细胞增殖平衡破坏时,可引起多种疾病的发生。 相似文献
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The cytokine tumor necrosis factor (TNF) is the primary trigger of inflammation. Like many extracellular signaling proteins, TNF is synthesized as a transmembrane protein; the active signal is its ectodomain, which is shed from cells after cleavage by an ADAM family metalloprotease, ADAM17 (TNFα-converting enzyme, TACE). We report that iRhom2 (RHBDF2), a proteolytically inactive member of the rhomboid family, is required for TNF release in mice. iRhom2 binds TACE and promotes its exit from the endoplasmic reticulum. The failure of TACE to exit the endoplasmic reticulum in the absence of iRhom2 prevents the furin-mediated maturation and trafficking of TACE to the cell surface, the site of TNF cleavage. Given the role of TNF in autoimmune and inflammatory diseases, iRhom2 may represent an attractive therapeutic target. 相似文献
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The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice 总被引:1,自引:0,他引:1
Tang W Lu Y Tian QY Zhang Y Guo FJ Liu GY Syed NM Lai Y Lin EA Kong L Su J Yin F Ding AH Zanin-Zhorov A Dustin ML Tao J Craft J Yin Z Feng JQ Abramson SB Yu XP Liu CJ 《Science (New York, N.Y.)》2011,332(6028):478-484
The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFα-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFα signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis. 相似文献
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Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing 总被引:1,自引:0,他引:1
Maeda S Hsu LC Liu H Bankston LA Iimura M Kagnoff MF Eckmann L Karin M 《Science (New York, N.Y.)》2005,307(5710):734-738
Variants of NOD2, an intracellular sensor of bacteria-derived muramyl dipeptide (MDP), increase susceptibility to Crohn's disease (CD). These variants are thought to be defective in activation of nuclear factor kappaB (NF-kappaB) and antibacterial defenses, but CD clinical specimens display elevated NF-kappaB activity. To illuminate the pathophysiological function of NOD2, we introduced such a variant to the mouse Nod2 locus. Mutant mice exhibited elevated NF-kappaB activation in response to MDP and more efficient processing and secretion of the cytokine interleukin-1beta (IL-1beta). These effects are linked to increased susceptibility to bacterial-induced intestinal inflammation and identify NOD2 as a positive regulator of NF-kappaB activation and IL-1beta secretion. 相似文献
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McIlwain DR Lang PA Maretzky T Hamada K Ohishi K Maney SK Berger T Murthy A Duncan G Xu HC Lang KS Häussinger D Wakeham A Itie-Youten A Khokha R Ohashi PS Blobel CP Mak TW 《Science (New York, N.Y.)》2012,335(6065):229-232
Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. A key mediator of septic shock is tumor necrosis factor-α (TNFα), which is shed from the plasma membrane after cleavage by the TNFα convertase (TACE). We report that the rhomboid family member iRhom2 interacted with TACE and regulated TNFα shedding. iRhom2 was critical for TACE maturation and trafficking to the cell surface in hematopoietic cells. Gene-targeted iRhom2-deficient mice showed reduced serum TNFα in response to lipopolysaccharide (LPS) and could survive a lethal LPS dose. Furthermore, iRhom2-deficient mice failed to control the replication of Listeria monocytogenes. Our study has identified iRhom2 as a regulator of innate immunity that may be an important target for modulating sepsis and pathogen defense. 相似文献
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Endothelial cell gene expression of a neutrophil chemotactic factor by TNF-alpha, LPS, and IL-1 beta 总被引:73,自引:0,他引:73
R M Strieter S L Kunkel H J Showell D G Remick S H Phan P A Ward R M Marks 《Science (New York, N.Y.)》1989,243(4897):1467-1469
Human endothelial cells produced a neutrophil chemotactic factor (NCF) upon stimulation with tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), or lipopolysaccharide (LPS). The expression of endothelial cell-derived NCF messenger RNA and biological activity was both time- and concentration-dependent. Maximal NCF mRNA expression occurred at 10 and at 2 nanograms per milliliter for TNF and IL-1 beta, respectively; mRNA expression was first observed 1 hour after stimulation and was maintained for at least 24 hours. In situ hybridization analysis showed that NCF mRNA peaked in treated cells by 24 hours, whereas unstimulated cells were negative. These studies demonstrated that endothelial cells may participate in neutrophil-mediated inflammation by synthesizing a chemotactic factor in response to specific monokines and LPS. 相似文献
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