Leung Kam
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Tumor necrosis factor (TNF) is a proinflammatory cytokine produced by macrophages, and it plays an important role in inflammation and immune response (1). There are two types of TNF (TNF-α, TNF-β). TNF-α is mainly responsible for initiating inflammatory responses by induction of several proinflammatory cytokines, chemokines, matrix metalloproteinases, and vascular endothelial adhesion molecules that attract leukocytes known to promote inflammation. There are two types of TNF receptors: TNFR1 and TNFR2. Soluble forms of TNF receptors are released upon proteolytic cleavage of the membrane-bound TNF receptors. Soluble TNF receptors participate in limiting the availability of TNF to bind to its receptors (2, 3). Several anti-TNF monoclonal antibodies (TNF blockers) to further reduce circulating TNF have been approved by the United States Food and Drug Administration (FDA) for the treatment of a variety of inflammatory diseases (4, 5). The interleukin-1 family consists of two proinflammatory cytokines, IL-1α and IL-1β, which bind to two IL-1 receptors (IL-1R1 and IL-1R2), and an IL-1R antagonist (IL-1ra), which is mainly produced by activated macrophages and tissue macrophages (6). IL-1α and IL-1β are important mediators of the inflammatory response and hematopoiesis, and they are involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis. IL-1 is involved in chronic inflammatory diseases and in neuropathological conditions (7, 8). The balancing act of IL-1 and IL-1ra plays an important role in the regulation of inflammation and immune responses (9). IL-1ra has been shown to be effective as an anti-inflammatory treatment in several chronic inflammatory diseases and stroke (10, 11). A human recombinant, non-glycosylated form of the human IL-1ra (rhIL-1ra, Anakinra) has been approved by the FDA for the treatment of rheumatoid arthritis (12). IL-1β and TNF-α exhibit additive or synergistic effects in promoting pathophysiological processes observed in many inflammatory diseases (13). A dual domain TNFR2-Fc-IL-1ra fusion protein was constructed by joining TNFR2 and IL-1ra cDNA to the Fc fragment of human IgG cDNA in an expression plasmid (14). The amino-terminal segment binds to TNF, and the carboxyl-terminal sequence binds to the IL-1R. Liu et al. (14) radiolabeled TNFR2-Fc-IL-1ra with Tc 2-iminothiolane reduction to produce Tc-TNFR2-Fc-IL-1ra for use with single-photon emission computed tomography (SPECT) imaging of inflammation in mice.
肿瘤坏死因子（TNF）是巨噬细胞产生的一种促炎细胞因子，在炎症和免疫反应中起重要作用（1）。TNF有两种类型（TNF-α、TNF-β）。TNF-α主要通过诱导多种促炎细胞因子、趋化因子、基质金属蛋白酶和血管内皮黏附分子来引发炎症反应，这些分子可吸引已知能促进炎症的白细胞。TNF受体有两种类型：TNFR1和TNFR2。可溶性TNF受体在膜结合型TNF受体经蛋白水解裂解后释放。可溶性TNF受体参与限制TNF与其受体结合的可利用性（2,3）。几种用于进一步降低循环TNF的抗TNF单克隆抗体（TNF阻滞剂）已获美国食品药品监督管理局（FDA）批准，用于治疗多种炎症性疾病（4,5）。白细胞介素-1家族由两种促炎细胞因子IL-1α和IL-1β组成，它们与两种IL-1受体（IL-1R1和IL-1R2）结合，还有一种IL-1受体拮抗剂（IL-1ra），主要由活化的巨噬细胞和组织巨噬细胞产生（6）。IL-1α和IL-1β是炎症反应和造血的重要介质，它们参与多种细胞活动，包括细胞增殖分化和凋亡。IL-1参与慢性炎症性疾病和神经病理状况（7,8）。IL-1和IL-1ra之间的平衡作用在炎症和免疫反应的调节中起重要作用（9）。在几种慢性炎症性疾病和中风中，IL-1ra已被证明作为抗炎治疗有效（10,11）。一种人重组、非糖基化形式的人IL-1ra（rhIL-1ra，阿那白滞素）已获FDA批准用于治疗类风湿关节炎（12）。在许多炎症性疾病中观察到的促进病理生理过程方面，IL-1β和TNF-α表现出相加或协同作用（13）。通过将TNFR2和IL-1ra cDNA连接到表达质粒中人IgG cDNA的Fc片段上，构建了一种双结构域TNFR2-Fc-IL-1ra融合蛋白（14）。氨基末端片段与TNF结合，羧基末端序列与IL-1R结合。Liu等人（14）用2-亚氨基硫杂环戊烷还原法用锝标记TNFR2-Fc-IL-1ra，以制备用于小鼠炎症单光子发射计算机断层扫描（SPECT）成像的锝-TNFR2-Fc-IL-1ra。
