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The Role of Tumor Necrosis Factor-Like Weak Inducer of Apoptosis in Atherosclerosis Via Its Two Different Receptors (Review)

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The Role of Tumor Necrosis Factor-Like Weak Inducer of Apoptosis in Atherosclerosis Via Its Two Different Receptors (Review) EXPERIMENTAL AND THERAPEUTIC MEDICINE 14: 891-897, 2017 The role of tumor necrosis factor-like weak inducer of apoptosis in atherosclerosis via its two different receptors (Review) HENGDAO LIU1,2, DAN LIN3, HONG XIANG1, WEI CHEN1, SHAOLI ZHAO1,4, HUI PENG1, JIE YANG1, PAN CHEN1, SHUHUA CHEN1 and HONGWEI LU1,2 1Center for Experimental Medical Research; 2Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013; 3Qingdao Center for Disease Control and Prevention, Qingdao, Shandong 266033; 4Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China Received May 3, 2016; Accepted March 31, 2017 DOI: 10.3892/etm.2017.4600 Abstract. At present, it is commonly accepted that athero- 1. Introduction sclerosis is a chronic inflammatory disease characterized by disorder of the arterial wall. As one of the inflammatory cyto- Atherosclerosis remains a major global challenge (1). The kines of the tumor necrosis factor superfamily, tumor necrosis World Health Organization statistics data suggest that, by factor-like weak inducer of apoptosis (TWEAK) participates 2020, atherosclerosis will be the most common cause of death in the formation and progression of atherosclerosis. TWEAK, and morbidity in both developed and developing countries (2). when binding to its initial receptor, fibroblast growth factor Atherosclerosis has long been studied as a chronic inflamma- inducible molecule 14 (Fn14), exerts adverse biological func- tory disorder of the arterial wall, which involves numerous tions in atherosclerosis, including dysfunction of endothelial cytokines. Accumulating data suggests that one of the cyto- cells, phenotypic change of smooth muscle cells and inflam- kines, tumor necrosis factor-like weak inducer of apoptosis matory responses of monocytes/macrophages. However, (TWEAK), is heavily involved in the formation and progres- accumulating data supports that, besides Fn14, TWEAK also sion of atherosclerosis (3-8). TWEAK is encoded by the binds to cluster of differentiation (CD)163, an anti‑inflamma- tumor necrosis factor ligand superfamily (TNFSF) member tory cytokine and a scavenger receptor exclusively expressed 12 gene in the tumor TNFSF and its role as a multifunctional by monocytes and macrophages. Furthermore, it has been cytokine was recognized in a previous study (9). Similar to demonstrated that CD163 is able to internalize TWEAK and other ligands of TNFSF, TWEAK is initially synthesized as likely elicits protective effects in atherosclerosis by termi- a type II transmembrane protein with 249 amino acids and is nating inflammation induced by TWEAK. In the present subsequently cut by furin to release smaller and soluble frag- study, the role of TWEAK in atherosclerosis was reviewed, ments known as sTWEAK, which mediate different biological with a predominant focus on CD163 and Fn14 receptors. effects (9-11). The role of TWEAK interactions with related receptors in atherosclerosis development have been elaborated by experiments in vitro and in vivo, and fibroblast growth Contents factor inducible molecule 14 (Fn14), the first reported receptor of TWEAK, is a related receptor (12-17). Another receptor, 1. Introduction cluster of differentiation (CD)163, has also been identified as 2. Fn14: The first definite receptor a receptor of TWEAK (18). CD163 is widely acknowledged as 3. CD163: The second definite receptor a scavenger receptor and an anti‑inflammatory molecule (18). 4. Therapeutic considerations Therefore, it is not surprising that there is now an increased 5. Conclusions interest in the interaction of TWEAK and CD163 in athero- sclerosis (19-21). In the present article, the function of Fn14 and CD163 receptors and TWEAK in atherosclerosis was investigated. Correspondence to: Professor Hongwei Lu, Center for Experimental Medical Research, The Third Xiangya Hospital 2. Fn14: The first definite receptor of Central South University, 138 Tong‑Zi‑Po Road, Changsha, Hunan 410013, P.R. China Fn14 expression and signaling. Fn14 was the first widely E‑mail: [email protected] recognized TWEAK receptor. Given its one single cysteine-rich domain (CRD), it is generally considered as the Key words: tumor necrosis factor-like weak inducer of apoptosis, smallest member of the tumor necrosis factor receptor (TNFR) fibroblast growth factor inducible molecule 14, cluster of superfamily (11). Originally, Fn14 was identified to be induced differentiation 163, receptor, atherosclerosis by fibroblast growth factor (FGF)1 (22) and subsequent studies discovered that various other growth factors, including FGF2, 892 LIU et al: TWEAK AND ITS RECEPTORS IN ATHEROSCLEROSIS platelet‑derived growth factor and epidermal growth factor, umbilical vein endothelial cells (HUVECs), which have been and cytokines such as tumor necrosis factor (TNF)‑α, inter- investigated in vitro (34). Furthermore, researchers have leukin (IL)-1β, transforming growth factor-β and interferon-γ, demonstrated that Fn14 mediates these processes by blocking are able to induce Fn14 expression (22-25). monoclonal antibody against human Fn14 (34). TWEAK and The chromosomal position of the human Fn14 gene is at Fn14 have been indicated in HUVECs to jointly induce mono- 16p13.3 (23). The Fn14 gene initially encodes a Fn14 type I cyte chemoattractant protein-1 (MCP-1) and IL-8 secretion, transmembrane 129‑amino acid protein that transforms to a which predominantly recruits monocytes and neutrophils (15) mature form (23). In the TNFR superfamily, the cytoplasmic (Fig. 1A). domain of Fn14 is the shortest, with only 28 amino acids (11). Similar to TNF‑α and other members in the family, Fn14 Phenotypic change of smooth muscle cells. Through contains a TNF receptor‑associated factor (TRAF) binding contraction, VSMCs partially maintain vascular tone and site that recruits and binds to TRAF adapter proteins (24). diameter (35). Contrary to skeletal and cardiac myocytes, The association may provoke the activation of nuclear factor VSMCs are not terminally differentiated and preserve (NF)‑κB. Notably, TWEAK, is able to induce prolonged remarkable phenotypic and functional plasticity in order to NF‑κB activation compared with TNF (26). respond to various stimuli (36). In developing atherosclerosis, In contrast to its substantial expression in injured and VSMCs in the quiescent ‘contractile’ phenotype are prone to morbid tissues, Fn14 is rarely expressed in healthy tissues, transform into the ‘proinflammatory’ phenotype; a pheno- which distinguishes it from TWEAK (26). Studies have type with a superior ability to proliferate and migrate (36). indicated that Fn14 is expressed in the liver following partial Previous studies have indicated that transformation to this hepatectomy and chemical injury (27,28), in the vasculature ‘novel’ VSMC phenotype may be elicited by TWEAK/Fn14 following balloon catheter injury (22), in the kidney after acute interaction (34,37,38). Therefore, we have reason to believe kidney injury and in the heart after myocardial infarction (29). that TWEAK/Fn14 interaction is involved in the formation of Regarding the vascular wall, Fn14 expression is scarce in atherosclerotic plaques by thickening neointimal. non-atherosclerotic arteries whereas TWEAK is typically Plaque rupture or erosion, secondary to complete or incom- expressed (15). However, in human atherosclerotic plaques, plete occlusive thrombosis, reflects the pathophysiological both TWEAK and Fn14 are expressed in vascular smooth process of an acute cardiovascular and cerebrovascular event muscle cells (VSMCs) and macrophages, suggesting that Fn14 related to atherosclerosis (14). Tissue factor (TF), plasminogen may interact with TWEAK on damaged vessel walls, which activator inhibitor 1 (PAI‑1) and various alternative molecules may lead to adverse outcomes in atherosclerotic lesions (30). are responsible for thrombosis, of which TF is the primary molecule involved in initiating a clotting cascade (39,40). TFs Fn14 in atherosclerosis. Atherosclerosis is generally consid- are identified in cellular pools in smooth muscle cells (SMCs) ered as a chronic inflammatory disease with dysfunction of and released in microparticles from SMCs (41). Compared to various cells, including macrophages, smooth muscle cells and SMCs in normal arterial tissue and adjacent media, PAI‑1 is endothelial cells (15,31,32). The interaction between TWEAK increasingly expressed in SMCs within the fibrous cap (42). and Fn14 may potentially stimulate the proliferation and migra- This increase in expression is critical for inhibiting fibrino- tion of cells and induce cell inflammatory responses, which are lysis (43,44). In human carotid atherosclerotic plaques, Fn14 critical steps in developing atherosclerotic plaques (32). The has been revealed to be colocalized with both PAI‑1 and joint function of TWEAK and Fn14 in disturbing endothelial TF (14). Similarly, in cultured human aortic SMCs, TWEAK cells, altering the phenotypes of smooth muscle cells and trig- has been observed to induce both TF and PAI‑1 expression gering the inflammatory response of monocytes/macrophages, and activation (14). Furthermore, with Fn14 small interfering respectively, will be discussed in subsequent sections. (si)RNA or an anti‑Fn14 blocking antibody, the increase in expression and activity of PAI‑1 and TF is curbed (Fig. 1B). Dysfunction of endothelial cells. Normal, healthy endothelium is characterized by its anticoagulant, antiplatelet and fibrinolytic Inflammatory
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