The Role of TIPE2 in the Regulation of Inflammation and Tumorigenesis

TIPE2 is a recently discovered regulator of immunity and inflammation. Here we describe a new function of TIPE2 in the regulation of Ras signaling and Tumorigenesis. By using various stimuli and inhibitors in T Cells and macrophages we discovered that TIPE2 is regulated at both the message and protein level by inflammatory stimuli. TIPE2 mRNA is regulated in the short to intermediate term by an NF-Kappa B induced micro RNA, and TIPE2 is also ubiquitylated and degraded, possibly by SCF-Beta TRCP. Mechanistically TIPE2 interacts with and inhibits the Ras-interacting domain of the RalGDS family of Ras effectors, leading to a loss of downstream Ral and AKT activity. TIPE2 deficiency led to increased activation of Ral and AKT, resulting in resistance to cell death, increased migration, and dysregulated exocyst complex formation. Overexpression of TIPE2 conversely induced cell death, affected actin polymerization, and reduced exocyst complex assembly. TIPE2 was able to dramatically slow the growth of Ras-induced tumors in mice, and the tumors were required to silence TIPE2 before they were licensed to grow. TIPE2 additionally negatively regulates effectors of the mTOR pathway, including S6K and 4EBP1, possibly via an interaction with, and destabilization of the mTORC2 complex. Crucially TIPE2 expression is either completely lost or heavily down-regulated by human hepatocellular carcinoma. Thus, via its simultaneous role as a regulator of inflammation and cancer, TIPE2 provides a mechanistic link between these two disease states, and may be a potential drug target for both inflammatory and neoplastic disease

TIPE2 regulates periodontal inflammation by inhibiting NF-κB p65 phosphorylation

The roles and molecular mechanisms of tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) in periodontitis remain largely unknown. Objective: This study aimed to determine the expression of TIPE2 and NF-κB p65 in rat Porphyromonas gingivalis-induced periodontics in vivo. Methodology: Periodontal inflammation and alveolar bone resorption were analyzed using western blotting, micro-computed tomography, TRAP staining, immunohistochemistry, and immunofluorescence. THP-1 monocytes were stimulated using 1 μg/ml Pg. lipopolysaccharide (Pg.LPS) to determine the expression of TIPE2 in vitro. TIPE2 mRNA was suppressed by siRNA transfection, and the transfection efficiency was proven using western blotting and real-time PCR. The NF-κB pathway was activated by treating the cells with 1 μg/ml Pg.LPS to explore related mechanisms. Results: The expression of both TIPE2 and NF-κB p65 was increased in the gingival tissues of rat periodontitis compared with normal tissues. Positive expression of TIPE2 was distributed in inflammatory infiltrating cells and osteoclasts in the marginal lacunae of the alveolar bone. However, strong positive expression of TIPE2 in THP-1 was downregulated after Pg.LPS stimulation. TIPE2 levels negatively correlated with TNF-α and IL-1β. Decreased TIPE2 in THP-1 further promoted NF-κB p65 phosphorylation. Mechanistically, TIPE2 knockdown upregulated NF-κB signaling pathway activity. Conclusions: Taken together, these findings demonstrate that TIPE2 knockdown aggravates periodontal inflammatory infiltration via NF-κB pathway. Interventions aimed at increasing TIPE2 may help in the therapeutic applications for periodontitis

TIPE2 promote synovial fibroblasts cell apoptosis of adjuvant arthritis rats by up-regulating caspase while down-regulating NF-κB

目的：TIPE2能够抑制炎症以及肿瘤的发生发展，并且TIPE2过表达能够促进细胞的凋亡。类风湿关节炎是一种免疫多态性慢性疾病，我们应用类风湿关节炎模型大鼠佐剂型关节炎滑膜成纤维样细胞(fibroblast-likesynoviocytesofratadjuvantarthritis，AA-FLS)，通过体外实验分析TIPE2对死亡受体5诱导细胞凋亡的作用探讨TIPE2对佐剂型关节炎发病的影响。 方法：通过RT-PCR、荧光实时定量PCR和Western-blotting技术检测正常大鼠滑膜成纤维样细胞以及AA-FLS中TIPE2的表达，明确TIPE2在两种细胞系的表达情况。进一步应用慢病毒载...Objective. The TIPE2 protein is an inhibitor of inflammation and cancer, and its overexpression induces cell death. We examined the role of TIPE2 with respect to adjuvant arthritis (AA)-associated mechanisms of pathogenesis. We also analyzed the TIPE2 regulation of DR5-mediated apoptosis in vitro during AA. Methods. We used semi-quantitative and quantitative reverse transcription- polymerase cha...学位：医学硕士院系专业：医学院_肿瘤学学号：2452012115323

Functions and associated mechanisms of Human tumor necrosis factor-alpha-induced protein 8 family during gastric cancer carcinogenesis

胃癌是消化系统最常见的恶性肿瘤，在世界范围内，胃癌的发病率居恶性肿瘤的第四位，死亡率居恶性肿瘤的第二位。胃癌发生、发展涉及多因素、多步骤、多基因参与的复杂过程，迄今为止，胃癌的病因和发病机制尚未完全阐明。因此，对胃癌发病机制、在不同分子途径在肿瘤发生发展中的作用机制的研究，寻找特异性的生物标志分子，对于早期发现胃癌和探寻新的治疗方法，进而提高胃癌患者生存率和提升生活质量具有重要意义。 TNFAIP8家族是由肿瘤坏死因子α诱导产生的一个蛋白质家族，参与多种生物学过程，并在许多疾病特别是自身免疫性疾病和肿瘤的发生、发展中发挥重要的作用，TNFAIP8、TIPE2、TIPE3是其中的重要成员。TN...Gastric cancer(GC) is a leading cause of global cancer mortality responsible for 700000 deaths annually, and still highly prevalent in many parts of Asia, Eastern Europe and South America. Most patients with GC are diagnosed at advanced disease stages, and overall 5-year survival rates for patients with resectable GC remain low at 10-30% despite clinical advances in surgery and therapy.The elucida...学位：理学博士院系专业：医学院_生理学学号：2452013015431

TIPE2在T细胞介导的心脏移植急性排斥反应中的潜在作用

目的探讨作为免疫负调控因子的肿瘤诱导坏死因子-α-诱导蛋白8样因子-2(TIPE2)在T细胞介导的小鼠心脏移植急性排斥反应中的潜在作用。方法通过苏木素-伊红(HE)染色和流式细胞术确定心脏移植物中的主要免疫排斥细胞,免疫荧光染色确定TIPE2与脾细胞间的关系,实时定量荧光PCR(Real-time PCR)检测心脏移植物TIPE2及细胞因子表达量。结果小鼠心脏移植7天后心脏组织出现明显免疫细胞浸润及心肌组织的破坏,流式细胞术检测心脏移植物中CD4~+和CD8~+T细胞增高,免疫荧光显示移植小鼠脾细胞中的CD4~+和CD8~+T细胞表达TIPE2,而心脏移植物在第7天时TIPE2和细胞因子表达量均明显增高。结论 TIPE2与在T细胞介导的小鼠心脏移植急性排斥反应中可能发挥着潜在作用。国家重点科学研究计划(2012CBA01303);;国家自然科学基金(31271038

TIPE family of proteins and its implications in different chronic diseases

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. The tumor necrosis factor-a-induced protein 8-like (TIPE/TNFAIP8) family is a recently identified family of proteins that is strongly associated with the regulation of immunity and tumorigenesis. This family is comprised of four members, namely, tumor necrosis factor-a-induced protein 8 (TIPE/TNFAIP8), tumor necrosis factor-a-induced protein 8-like 1 (TIPE1/TNFAIP8L1), tumor necrosis factor-a-induced protein 8-like 2 (TIPE2/TNFAIP8L2), and tumor necrosis factor-a-induced protein 8-like 3 (TIPE3/TNFAIP8L3). Although the proteins of this family were initially described as regulators of tumorigenesis, inflammation, and cell death, they are also found to be involved in the regulation of autophagy and the transfer of lipid secondary messengers, besides contributing to immune function and homeostasis. Interestingly, despite the existence of a significant sequence homology among the four members of this family, they are involved in different biological activities and also exhibit remarkable variability of expression. Furthermore, this family of proteins is highly deregulated in different human cancers and various chronic diseases. This review summarizes the vivid role of the TIPE family of proteins and its association with various signaling cascades in diverse chronic diseases

The role of TNFAIP8 family in gastric cancer and heart transplantation

摘要 目的：TIPE及TIPE2是TNFAIP8（Tumornecrosisfactor-αinducedprotein-8，TIPE，TNFAIP8）家族的重要成员，TIPE是调控凋亡进程的重要分子，本研究之一是应用TIPE不同表达的BGC823细胞株建立胃癌裸鼠移植瘤模型，观察TIPE对移植瘤生长的影响；同时收集并检测胃癌临床标本TIPE的表达特点，分析TIPE与胃癌临床病理特征的关系，明确TIPE与胃癌生物学行为的关系及对胃癌生长的影响。 TIPE2为免疫负性调控因子，对免疫稳态的维持起重要作用。本研究之二为构建异种心脏移植模型，在移植后的不同时间点收集移植物和脾脏组织，检测TIPE...ABSTRACT Objective: As is known, TIPE and TIPE2 are important members of TNFAIP8（Tumor necrosis factor-α induced protein-8,TIPE,TNFAIP8） family. Since TIPE is a recently discovered antiapoptotic molecule, part of this study focuses on constructing a nude-mouse transplanted tumor model with the BGC823 cell strain--different expression of TIPE, and observing the influences TIPE has on the growth of...学位：医学硕士院系专业：医学院_外科学学号：2452013115349

PENGARUH JALAN KAKI TERHADAP KADAR GULA DARAH PADA PENDERITA DIABETES MELLITUS TIPE2 DI DESA BAJARBILLAH TAMBELANGAN KAB SAMPANG

Diabetes Mellitus merupakan golongan penyakit kronis yang salah satunya di sebabkan karena kurangnya aktifitas pisik yang akan meningkatan kadar gula darah. Latihan fisik adalah salah satu penatalaksanaan diabetes mellitus karena dapat menurunkan kadar gula dalam darah. Tujuan Penelitian adalah menganalisis pengaruh antara terapi jalan kaki dengan kadar glukosa darah pada penderita Diabetes Mellitus tipe2. Desain penelitian ini adalah Quasy Experiment dengan rancangan pre-post control group design dengan populasi sebagian penderita diabetes mellitus tipe2 di Desa Banjarbillah diambil dengan teknik simple random sampling. Variabel independen jalan kaki, sedangkan variable dependen kadar gula darah. Instrumen pengambilan data adalah checklist, alat cek gula darah, selanjutnya data dianalisis menggunakan uji Mann-Whitney. Hasil penelitian menunjukan bahwa nilai rata rata gula darah kelompok perlakuan pre 205.1 mg/dl dan post 173.8 mg/dl. Pada kelompok kontrol nilai gula darah pre 193.2 mg/dl dan post 195 mg/dl. Terdapat penurunan nilai gula darah pada kelompok perlakuan dan tidaka ada penurunan pada kelompok kontrol. Artinya ada pengaruh jalan terhadap penurunan gula darah pada pasien diabetes mellitus tipe2. Simpulan dari penelitian ini yaitu ada pengaruh antara terapi jalan kaki terhadap penurunan kadar gula darah. bagi pasien diabetes mellitus tipe2 perlu perlu di lakukan secara menerus dan teratur