LaMarre J, Wollenberg G K, Gonias S L, Hayes M A
Department of Pathology, University of Guelph, Ontario, Canada.
Lab Invest. 1991 Jul;65(1):3-14.
Multiple mechanisms are necessary to spatially and temporally restrict and direct the effects of potent mediators of inflammation, immune reactions and tissue repair. Recent studies implicate alpha 2-macroglobulin (alpha 2M) as a protein that regulates the distribution and activity of many cytokines, including transforming growth factors-beta (TGFs-beta), tumor necrosis factor-alpha (TNF-alpha), platelet derived growth factor (PDGF), interleukin-6 (IL-6), nerve growth factor (NGF), fibroblast growth factor (b-FGF), and interleukin-1 beta (IL-1 beta). Some cytokines, including PDGF, NGF, and IL-6 bind preferentially to the native secreted form of alpha 2M, whereas the TGF-beta s, TNF-alpha and IL-1 beta bind preferentially to forms of alpha 2M that have been modified by proteinases such as plasmin. Cytokines bound to native alpha 2M retain much of their biologic activity in various bioassays, whereas cytokines bound to "activated" alpha 2Ms have decreased activity in some cell systems. Because native alpha 2M in circulation can escape into extravascular fluid during tissue injury and inflammation, alpha 2M is a putative cytokine carrier, especially in the presence of heparin or specific cytokine receptors that can displace non-covalently bound cytokines from native alpha 2M. However, proteinase or chemically modified alpha 2Ms become activated for receptor-mediated endocytosis (RME) when they undergo conformational alterations that expose a latent alpha 2M receptor-recognition domain. Circulating activated alpha 2Ms, together with bound cytokines, are rapidly removed by hepatic alpha 2M-receptors (alpha 2M-R) but also bind to other cells expressing alpha 2M-R. This suggests that diseases resulting from an apparent change in the production of one or several different cytokines might represent changes in either the production of alpha 2M "cytokine scavengers" or their alpha 2M-receptor-mediated clearance/targeting mechanisms. The sequence identity between the LDL-receptor related protein and the alpha 2M receptor (115) provides a theoretical basis for interference with cytokine clearance by association of competing lipoprotein ligands with this cytokine clearance pathway. Furthermore, activated alpha 2Ms or augmentation of alpha 2M-receptor-dependent cytokine clearance might be novel strategies for preventing the harmful systemic or local effects of excess cytokines such as TGF-beta s and TNF-alpha in vivo.
需要多种机制在空间和时间上限制并引导炎症、免疫反应及组织修复的强效介质发挥作用。最近的研究表明，α2巨球蛋白（α2M）是一种能调节多种细胞因子分布和活性的蛋白质，这些细胞因子包括转化生长因子-β（TGF-βs）、肿瘤坏死因子-α（TNF-α）、血小板衍生生长因子（PDGF）、白细胞介素-6（IL-6）、神经生长因子（NGF）、成纤维细胞生长因子（b-FGF）以及白细胞介素-1β（IL-1β）。一些细胞因子，如PDGF、NGF和IL-6，优先与天然分泌形式的α2M结合，而TGF-βs、TNF-α和IL-1β则优先与经纤溶酶等蛋白酶修饰的α2M形式结合。与天然α2M结合的细胞因子在各种生物测定中仍保留其大部分生物活性，而与“活化”α2M结合的细胞因子在某些细胞系统中的活性则降低。由于循环中的天然α2M在组织损伤和炎症期间可逸出到血管外液中，α2M是一种假定的细胞因子载体，尤其是在存在肝素或特定细胞因子受体的情况下，这些受体可将非共价结合的细胞因子从天然α2M上置换下来。然而，蛋白酶或化学修饰的α2M在经历构象改变从而暴露出潜在的α2M受体识别域时，会被激活以进行受体介导的内吞作用（RME）。循环中的活化α2M与结合的细胞因子一起，会被肝脏的α2M受体（α2M-R）迅速清除，但也会与表达α2M-R的其他细胞结合。这表明，由一种或几种不同细胞因子产生的明显变化所导致的疾病，可能代表着α2M“细胞因子清除剂”的产生变化，或者其α2M受体介导的清除/靶向机制发生了变化。低密度脂蛋白受体相关蛋白与α2M受体之间的序列同一性（115）为通过竞争性脂蛋白配体与该细胞因子清除途径结合来干扰细胞因子清除提供了理论基础。此外，活化的α2M或增强α2M受体依赖性细胞因子清除可能是预防体内过量细胞因子（如TGF-βs和TNF-α）产生有害全身或局部效应的新策略。
