Immunological function of transmembrane TNF-alpha

跨膜型肿瘤坏死因子-α是可溶型肿瘤坏死因子-α的前体，表达于活化的巨噬细胞和淋巴细胞以及其他类型的细胞。经肿瘤坏死因子-α转换酶(TACE)处理后，可溶性的肿瘤坏死因子从跨膜的肿瘤坏死因子中被切割出来，并通过与远端组织的1型和2型肿瘤坏死因子受体(肿瘤坏死因子受体1、2受体)结合来调节其生物学活性。越来越多的证据表明，不仅可溶性肿瘤坏死因子参与了炎症反应，跨膜型肿瘤坏死因子也参与了炎症反应。肿瘤坏死因子拮抗剂因其在活动性慢性炎症性疾病中的显著临床疗效而备受关注。在类风湿关节炎中，英夫利昔单抗、人源化抗肿瘤坏死因子α抗体和依那西普均有效，而在克罗恩病中，只有英夫利昔单抗和阿达莫单抗能诱导临床缓解。此外，英夫利昔单抗和阿达利单抗更容易引起粒细胞…。更严重的感染，如肺结核。考虑到跨膜型肿瘤坏死因子在肉芽肿性炎症中的重要作用，分析跨膜型肿瘤坏死因子的生物学特性及其与肿瘤坏死因子拮抗剂的相互作用将有助于了解这些有前景的治疗模式的不同临床疗效的基础。英利昔单抗、阿达单抗和依那西普在表达肿瘤坏死因子的人T细胞中类似地诱导抗体依赖的戴尔介导的细胞毒(ADCC)，而只有英夫利昔单抗和阿达利单抗表现出补体依赖性细胞毒(CDC)和内外信号(反向信号)和依那西普。另外，英夫利昔单抗和阿达单抗均能有效抑制跨膜型肿瘤坏死因子作为配体的功能，而依那西普则不能。基因芯片揭示了英夫利昔单抗通过跨膜肿瘤坏死因子介导的细胞内信号。其中49个分子表达上调，240个分子表达下调，提示不同的肿瘤坏死因子拮抗剂(英夫利昔单抗、阿达莫单抗、依那西普)抗跨膜型肿瘤坏死因子活性的差异可能与其不同的临床疗效有关。较少

Transmembrane TNF-alpha, a precursor of soluble form of TNF-alpha (TNF), is expressed on activated macrophages and lymphocytes as well as other cell types. After processed by TNF-alpha-converting enzyme (TACE), soluble form of TNF is cleaved from transmembrane TNF and mediates its biological activities through binding to type 1 and type 2 TNF receptors (TNF-R1, TNF-R2) of remote tissues. Accumulating evidence suggests that not only soluble TNF, but also transmembrane TNF is involved in the inflammatory response. TNF antagonists are the center of attention for their dramatic clinical efficacy in active chronic inflammatory diseases. In rheumatoid arthritis, both infliximab (chimeric anti-TNF antibody), adalimumab (humanized anti-TNF-alpha antibody) and etanercept (p75 TNF-alpha receptor-IgG Fc fusion protein) are highly effective, while in Crohn's disease, only infliximab and adalimumab can induce clinical remission. In addition, infliximab and adalimumab are more prone to cause granulo … More matous infections such as tuberculosis. Considering the important role of transmembrane TNF in granulomatous inflammation, analysing the biology of transmembrane TNF and its interaction with TNF antagonists will contribute to understand the bases for differential clinical efficacies of these promising treatment modalities.Infliximab, adalimumab, and etanercept similarly induced antibody-dependent dell-mediated cytotoxicity (ADCC) in transmembrane TNF-expressing human T cells, however only infliximab and adalimumab showed complement-dependent cytotoxicity (CDC) and outside-to-inside signal (reverse signal) and etanercept did not. In addition, the function of transmembrane TNF as a ligand detected by cytotoxic activity against TNF recetor-bearing T cells was effectively inhibited by infliximab and adalimumab, but not by etanercept. cDNA array revealed the intracellular signals mediated by infliximab through transmembrane TNF. mRNA of 49 molecules was upregulated, while mRNA of 240 molecules was downregulated.These results indicate that the difference in the activity against transmembrane TNF among TNF antagonists (infliximab, adalimumab, etanercept) is involved in the differential clinical efficacies of these TNF antagonists. Less