Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents.
Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents.
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DOI：
10.1093/rheumatology/keq031
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发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Shimoda T
中科院分区：
文献类型：
--
作者：
Horiuchi T;Mitoma H;Harashima S;Tsukamoto H;Shimoda T
跨膜TNF-α是可溶性TNF-α的前体，在活化的巨噬细胞和淋巴细胞以及其他细胞类型上表达。经TNF-α转化酶（TACE）处理后，可溶性形式的TNF-α从跨膜TNF-α上裂解，并通过与远端组织的1型和2型TNF受体（TNF-R1和-R2）结合介导其生物学活性。越来越多的证据表明，不仅可溶性TNF-α，而且跨膜TNF-α参与炎症反应。跨膜TNF-α作为双极分子，以细胞与细胞接触的方式作为配体和受体传递信号。产生TNF-α的细胞上的跨膜TNF-α与TNF-R1和TNF-R2结合，并作为配体将信号传递给靶细胞，而跨膜TNF-α也作为受体，在与其天然受体结合后将由外向内（反向）信号传递回细胞。抗TNF药物英夫利西单抗、阿达木单抗和依那西普可结合并中和可溶性TNF-α，但对跨膜TNF-α表达细胞（TNF-α产生细胞）的作用不同。在临床环境中，这三种抗TNF药物对RA同样有效，但依那西普对肉芽肿性疾病无效。此外，英夫利西单抗诱导肉芽肿感染的频率高于依那西普。考虑到跨膜TNF-α在肉芽肿性炎症中的重要作用，综述跨膜TNF-α的生物学及其与抗TNF药物的相互作用将有助于理解这些有前途的治疗方式的临床疗效差异的基础。
Transmembrane TNF-α, a precursor of the soluble form of TNF-α, is expressed on activated macrophages and lymphocytes as well as other cell types. After processing by TNF-α-converting enzyme (TACE), the soluble form of TNF-α is cleaved from transmembrane TNF-α and mediates its biological activities through binding to Types 1 and 2 TNF receptors (TNF-R1 and -R2) of remote tissues. Accumulating evidence suggests that not only soluble TNF-α, but also transmembrane TNF-α is involved in the inflammatory response. Transmembrane TNF-α acts as a bipolar molecule that transmits signals both as a ligand and as a receptor in a cell-to-cell contact fashion. Transmembrane TNF-α on TNF-α-producing cells binds to TNF-R1 and -R2, and transmits signals to the target cells as a ligand, whereas transmembrane TNF-α also acts as a receptor that transmits outside-to-inside (reverse) signals back to the cells after binding to its native receptors. Anti-TNF agents infliximab, adalimumab and etanercept bind to and neutralize soluble TNF-α, but exert different effects on transmembrane TNF-α-expressing cells (TNF-α-producing cells). In the clinical settings, these three anti-TNF agents are equally effective for RA, but etanercept is not effective for granulomatous diseases. Moreover, infliximab induces granulomatous infections more frequently than etanercept. Considering the important role of transmembrane TNF-α in granulomatous inflammation, reviewing the biology of transmembrane TNF-α and its interaction with anti-TNF agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities.
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