Evidence of a mechanism by which etanercept increased TNF-alpha in multiple myeloma: New insights into the biology of TNF-alpha giving new treatment opportunities-the role of bupropion
Evidence of a mechanism by which etanercept increased TNF-alpha in multiple myeloma: New insights into the biology of TNF-alpha giving new treatment opportunities-the role of bupropion
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DOI：
10.1016/j.leukres.2005.05.006
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发表时间：
2005-12-01
影响因子：
2.7
通讯作者：
Kast, RE
中科院分区：
文献类型：
--
作者：
Kast, RE
依那西普是一种市售的药物蛋白，被批准用于治疗类风湿性关节炎。皮下给予依那西普结合并灭活可溶性肿瘤坏死因子α (TNF)，依那西普具有良好的安全性记录，有利于减轻RA患者的疼痛、炎症和关节破坏。RA是由多种因素介导的，TNF就是其中之一。恶性骨髓瘤，MM，是生发后中心B淋巴细胞的恶性克隆扩增。由于TNF是MM细胞增殖和维持所必需的生长因子，而依那西普与可溶性TNF结合，在RA中具有临床益处，因此在MM中进行了依那西普的实验。与预期相反，依那西普导致TNF水平升高，并可能缩短生存期。本文提出了一个关于这是如何发生的假设。TNF有两种同源受体，称为R1和R2， TNF有两种形式，可溶性和跨膜。可溶性TNF对TNF- r1的亲和力大于对TNF- r2的亲和力。跨膜TNF对这两种受体具有相同的亲和力。由于TNF- r2信号比TNF- r1更倾向于抗凋亡和激活核因子κ B (NFkB)，而TNF- r1比TNF- r2更倾向于促凋亡，通过灭活可溶性时间而保持跨膜TNF信号相对不变，依那西普改变了TNF- r1向TNF- r2信号的权重平衡。抗细胞凋亡和肿瘤坏死因子的合成会因这种转变而上调。早期资料表明，常见的通用抗抑郁药安非他酮可能通过下调肿瘤坏死因子的合成来改善克罗恩病的病程，可能也会减缓MM的病程。(C) 2005 Elsevier Ltd版权所有。
Etanercept is a commercially available pharmaceutical protein approved for treatment of rheumatoid arthritis, RA. Given subcutaneously, etanercept binds and inactivates soluble tumor necrosis factor-alpha, TNF, Etanercept has a good safety record and is of benefit in lowering pain, inflammation, and joint destruction in RA. RA is mediated by many factors, TNF among them. Malignant myeloma, MM, is a malignant clonal expansion of a post-germinal center B lymphocyte. Since TNF is a necessary growth factor for expansion and maintenance of MM cells, and etanercept binds soluble TNF and is of clinical benefit in RA, etanercept was tried experimentally in MM. Contrary to expectations, etanercept resulted in increased levels of TNF and possibly shortened survival. This paper presents an hypothesis of how this happened. There are two cognate receptors for TNF, termed R1 and R2 and two forms of TNF, soluble and transmembrane. Soluble TNF has greater affinity for TNF-R1 than for TNF-R2. Transmembrane TNF has equal affinity for the two receptors. Since TNF-R2 signaling tends to be more anti-apoptotic and activating of nuclear factor kappa B, NFkB, than is TNF-R1, and TNF-R1 tends to be more pro-apoptotic than is TNF-R2, by inactivating soluble TINE while leaving transmembrane TNF signaling relatively unchanged, etanercept changed the balance in TNF signaling from TNF-R1 towards TNF-R2 weighting. Anti-apoptosis and TNF synthesis Would have been up-regulated by that shift. Early data indicates that the common generic antidepressant bupropion may ameliorate Crohn's disease course by down regulating TNF synthesis, maybe it will slow the course of MM as well. (C) 2005 Elsevier Ltd. All rights reserved.