TWEAK Proteins  (TWEAK 蛋白)

TWEAK 蛋白是细胞因子肿瘤坏死因子样的细胞凋亡弱诱导因子。它是一种属于肿瘤坏死因子 (TNF) 超家族的多功能细胞因子，通过结合 TweakR/Fn14 受体发挥作用。TWEAK 蛋白是一种细胞表面相关的 II 型跨膜蛋白，可断裂为两种肽链类型：膜型和分泌型 (或可溶性形态)。可溶性形态由蛋白水解过程的膜形态衍生而来。人与小鼠的蛋白序列差异很大，相似度为 24.79%^[1]。TWEAK 蛋白与 FN14 结合，也可能与 TNRFSF12/APO3 结合，在某些细胞类型中是一种弱凋亡诱导剂。TWEAK 蛋白可介导 NF-κ-B 的激活，促进血管生成和内皮细胞的增殖^[2]。TWEAK 蛋白具有多种生物活性，其中许多与免疫系统的发育和功能有关。TWEAK 蛋白对某些特定的人肿瘤细胞系和单核细胞具有促凋亡活性，同时促进人血管内皮细胞 (ECs) 和平滑肌细胞 (SMCs) 的细胞增殖。此外，FGF-2 联合治疗可以增强微调刺激的HUVEC增殖，这可能是由于 FGF-2 能够上调 TWEAK/Fn14 基因表达。同时，TWEAK-TweakR/Fn14 自分泌信号通路促进人微血管肾内皮细胞 (HMREC) 迁移^[1]。TWEAK 蛋白在炎症反应中也起着关键作用。TWEAK 蛋白能刺激人肿瘤细胞系、WI-38 成纤维细胞和星形胶质细胞中白细胞介素 (IL)-8 的分泌。TWEAK 蛋白还能增加星形胶质细胞中 IL-6 的分泌和 ICAM-1 的表达。此外，联合培养 TWEAK 蛋白可增强 TNF 和 IL-1 的促炎活性，说明 TWEAK 蛋白可能参与慢性炎性疾病的发病机制^[3]。总之，TWEAK 蛋白涉及刺激细胞生长和血管生成，诱导炎症细胞因子，在某些实验条件下，刺激细胞凋亡^[1]。

TWEAK Protein refers to the cytokine tumor necrosis factor-like weak inducer of apoptosis. It is a multifunctional cytokine belonging to tumor necrosis factor (TNF) superfamily, acts function by binding TweakR/Fn14 receptor. TWEAK is a cell surface-associated type II transmembrane protein with 2 types protein chain: the membrane form and the secreted or soluble form. The soluble form derives from the membrane form by proteolytic processing. The protein sequences in human and mouse is very different with similarity of 24.79%^[1]. TWEAK binds to FN14 and possibly also to TNRFSF12/APO3, is a weak inducer of apoptosis in some cell types. TWEAK mediates NF-kappa-B activation, promotes angiogenesis and the proliferation of endothelial cells^[2]. TWEAK has multiple biological activities, many of which are associated with immune system development and function. TWEAK does have pro-apoptotic activity on a select group of human tumor cell lines and on monocytes, while it promotes cell proliferation in human vascular endothelial cells (ECs) and smooth muscle cells (SMCs). Furthermore, FGF-2 co-treatment can potentiate TWEAK-stimulated HUVEC proliferation, an effect that may be due to the ability of FGF-2 to up-regulate TweakR/Fn14 gene expression. At the meanwhile TWEAK-TweakR/Fn14 autocrine signaling promotes human microvascular renal EC (HMREC) migration^[1]. TWEAK also plays key role in inflammatory response. TWEAK, stimulates interleukin (IL)-8 secretion in human tumor cell lines, WI-38 fibroblasts and astrocytes. TWEAK also increases IL-6 secretion and ICAM-1 expression in astrocyte cell. Moreover, TWEAK co-incubation could potentiate the pro-inflammatory activities of TNF and IL-1, and concluded that TWEAK could be involved in the pathogenesis of chronic inflammatory diseases^[3]. Above all, TWEAK involves in stimulation of cell growth and angiogenesis, induction of inflammatory cytokines, and under some experimental conditions, stimulation of apoptosis^[1].

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