Tumor Necrosis Factor-α-induced Protein 8 Research Articles

Synovial fluid exosome-derived miR-182-5p alleviates osteoarthritis by downregulating TNFAIP8 and promoting autophagy through LC3 signaling

ObjectiveTo investigate the role of exosomal miRNAs from synovial fluid (SF) in osteoarthritis (OA) patients and investigate the underlying molecular mechanism. MethodsDegenerated knee tissues were collected from male and female OA patients. Enzyme-linked immunosorbent assay (ELISA) was used to detect the differences in the expression of inflammatory indicators, including TNF-α, IL-6, and IL-10, between the degenerative and injury groups. Exosomes were isolated from SF using the Exoquick kit, and a microarray was used to identify differentially expressed miRNAs (DEmiRNAs), which were analyzed using bioinformatics. The predicted relationship between DEmiRNAs and target genes was verified using a luciferase reporter gene assay. CCK-8 and transwell assays were used to assess cell viability and migration. Immunofluorescence and TUNEL assay were used to detect cell autophagy and apoptosis. The interaction between proteins was detected by immunoprecipitation and verified by Mab rescue assay. ResultsThe relative expression of TNF-α/IL6 was significantly higher in the degeneration group than in the injury group. The OA degeneration group released significantly more and smaller exosomes than the injury group. The expression of miR-182-5p was markedly reduced in OA patients and had a higher correlation with inflammatory indicators. Tumor necrosis factor α-induced protein 8 (TNFAIP8) was a target of miR-182-5p, and its overexpression promoted chondrocyte proliferation, migration, and invasion and enhanced the wound healing efficiency. We also found a direct interaction of TNFAIP8 with autophagy-related gene 3 (ATG3). TNFAIP8 triggered ATG3 LC3-mediated autophagy. ConclusionThe downregulation of exosomal miR-182-5p inhibits OA degeneration by targeting TNFAIP8 via the ATG/LC3 pathway.

Kidney tubular epithelial cells control interstitial fibroblast fate by releasing TNFAIP8-encapsulated exosomes

Kidney fibrosis, characterized by the activation and expansion of the matrix-producing fibroblasts, is the common outcome of chronic kidney disease (CKD). While fibroblast proliferation is well studied in CKD, little is known about the regulation and mechanism of fibroblast depletion. Here, we show that exosomes derived from stressed/injured tubules play a pivotal role in dictating fibroblast apoptosis and fate. When human kidney tubular cells (HK-2) were stimulated with TGF-β1, they produced and released increased amounts of exosomes (TGFβ-Exo), which prevented renal interstitial fibroblasts from apoptosis. In vivo, injections of TGFβ-Exo promoted renal fibroblast survival, whereas blockade of exosome secretion accelerated fibroblast apoptosis in obstructive nephropathy. Proteomics profiling identified the tumor necrosis factor-α-induced protein 8 (TNFAIP8) as a key component enriched in TGFβ-Exo. TNFAIP8 was induced in renal tubular epithelium and enriched in the exosomes from fibrotic kidneys. Knockdown of TNFAIP8 in tubular cells abolished the ability of TGFβ-Exo to prevent fibroblast apoptosis. In vivo, gain- or loss- of TNFAIP8 prevented or aggravated renal fibroblast apoptosis after obstructive injury. Mechanistically, exosomal-TNFAIP8 promoted p53 ubiquitination leading to its degradation, thereby inhibiting fibroblasts apoptosis and inducing their proliferation. Collectively, these results indicate that tubule-derived exosomes play a critical role in controlling the size of fibroblast population during renal fibrogenesis through shuttling TNFAIP8 to block p53 signaling. Strategies to target exosomes may be effective strategies for the therapy of fibrotic CKD.

Research progress of TIPE2 in immune-related diseases.

The tumor necrosis factor α-induced protein 8 (TNFAIP8) family, which consists of TNFAIP8 (TIPE), TNFAIP8L1 (TIPE1), TNFAIP8L2 (TIPE2) and TNFAIP8L3 (TIPE3), has recently emerged as a regulatory factor involved in immune response and tumorigenesis. Among its members, TIPE2 acts as a negative regulator of both innate and adaptive immunity, playing a crucial role in maintaining immune homeostasis by negatively regulating T cell receptor (TCR) and toll-like receptor (TLR) signal transduction. Immune homeostasis is an indispensable characteristic of the immune system, which prevents harmful inflammatory reactions and ensures the proper functioning of the body. A large number of studies have shown that abnormal TIPE2 expression exists in a variety of inflammation-related diseases such as asthma, colitis, and systemic lupus erythematosus, highlighting the importance of comprehending its function for the prevention and treatment of immune-related conditions. This review aims to provide an overview of the in vivo distribution and expression of TIPE2, its regulatory role in central and peripheral immune-related diseases, and the underlying mechanisms that govern its function in the inflammatory response. By delving into these aspects, a deeper understanding of the role and functionality of TIPE2 in inflammatory responses can be achieved.

TNFAIP8 modulates the survival and immune activity of Th17 cells via p53/ p21/ MDM2 pathway after acute insult

Th17 cells induced immunosuppression plays a vital role in sepsis. As a member of the tumor necrosis factor α induced protein 8 (TNFAIP8) family, TNFAIP8 is associated with different physiopathological conditions with immunological responses. However, its potential roles in regulating Th17 cells after the acute insult have not been fully elucidated. In this study, sepsis was induced by cecal ligation and puncture (CLP) in the male adult C57BL/6 mice. The stable TNFAIP8 knockdown (KD) Th17 cells were established by infecting with lentivirus carrying TNFAIP8-specific shRNA. CCK-8 assay was conducted to evaluate Th17 cell proliferation, and Annexin V/7-AAD assay was applied for apoptosis measurement by flow cytometry. The alterations of p53/ p21/ MDM2 pathway were assessed by Western blot. We observed that a high TNFAIP8 expression level was related to acute injury in septic mice. TNFAIP8 silencing suppressed Th17 cell proliferation and cytokine production in vivo and in vitro. In addition, TNFAIP8 KD increased Th17 cell apoptosis in septic mice. Furthermore, TNFAIP8 seems to affect the immune function of Th17 cells by regulating p53/ p21/ MDM2 signaling processes. We found that TNFAIP8 KD caused the up-regulation of P21 and MDM2, and also elevated p53 protein level during sepsis. Pharmacological inhibition of p53 partially rescued cell proliferation and apoptotic effects of TNFAIP8 KD. In summary, our work suggests that TNFAIP8 modulates the survival and immune function of Th17 cells after acute insult, which was possibly mediated through the p53/ p21/ MDM2 pathway.

Identification of TNFAIP8 as an Immune-Related Biomarker Associated With Tumorigenesis and Prognosis in Cutaneous Melanoma Patients.

Tumor necrosis factor-α–induced protein 8 (TNFAIP8) is a member of the TIPE/TNFAIP8 family which is associated with inflammation and tumorigenesis. The potential role of TNFAIP8 in a tumor immune microenvironment in skin cutaneous melanoma (SKCM) has not yet been investigated. The TNFAIP8 expression was evaluated via gene expression profiling interactive analysis (GEPIA). We also evaluated the influence of TNFAIP8 on overall survival via GEPIA and PrognoScan. After GO and KEGG pathway analyses, the correlation between the TNFAIP8 expression level and immune cells or gene markers of the immune infiltration level was explored by R-language. The result showed the TNFAIP8 expression was significantly reduced in SKCM in comparison with normal control. In SKCM, the TNFAIP8 expression in higher levels was associated with the better overall survival. The high expression of TNFAIP8 was positively correlated with the immune score and promoted immune cell infiltration in SKCM patients. TNFAIP8 can be a positive prognosis marker or new immunotherapy target in SKCM.

Decoupling tumor cell metastasis from growth by cellular pilot protein TNFAIP8.

Cancer metastasis accounts for nearly 90% of all cancer deaths. Metastatic cancer progression requires both cancer cell migration to the site of the metastasis and subsequent proliferation after colonization. However, it has long been recognized that cancer cell migration and proliferation can be uncoupled; but the mechanism underlying this paradox is not well understood. Here we report that TNFAIP8 (tumor necrosis factor-α-induced protein 8), a "professional" transfer protein of phosphoinositide second messengers, promotes cancer cell migration or metastasis but inhibits its proliferation or cancer growth. TNFAIP8-deficient mice developed larger tumors, but TNFAIP8-deficient tumor cells completely lost their ability to migrate toward chemoattractants and were defective in colonizing lung tissues as compared to wild-type counterparts. Mechanistically, TNFAIP8 served as a cellular "pilot" of tumor cell migration by locally amplifying PI3K-AKT and Rac signals on the cell membrane facing chemoattractant; at the same time, TNFAIP8 also acted as a global inhibitor of tumor cell growth and proliferation by regulating Hippo signaling pathway. These findings help explain the migration-proliferation paradox of cancer cells that characterizes many cancers.

Knockdown of circ_0004104 Alleviates Oxidized Low-Density Lipoprotein-Induced Vascular Endothelial Cell Injury by Regulating miR-100/TNFAIP8 Axis.

Coronary artery disease (CAD) is a common cardiovascular disease, mainly due to vascular endothelial cell (VEC) injury caused by atherosclerosis. Circular RNA has been shown to be involved in the regulation of various diseases. However, the role and mechanism of circ_0004104 in CAD are still unclear. Oxidized low-density lipoprotein (ox-LDL) was used to construct the VEC injury model in vitro. The expression levels of circ_0004104 and miR-100 were measured by quantitative real-time polymerase chain reaction. The proliferation of VECs was determined using 3-(45)-dimethylthiahiazo (-z-y1)-35-di-phenytetrazoliumromide assay and 5-ethynyl-2'-deoxyuridine staining assay. VEC apoptosis rate was assessed using flow cytometry, and caspase-3 activity was measured using a Caspase-3 Assay Kit. The protein expression levels of Ki-67, cleaved-caspase3, and tumor necrosis factor-α-induced protein 8 (TNFAIP8) were detected by western blot analysis. Furthermore, enzyme-linked immunosorbent assay was performed to assess the concentrations of inflammatory cytokines. In addition, the relationship between miR-100 and circ_0004104 or TNFAIP8 was confirmed by dual-luciferase reporter assay and biotin-labeled RNA pull-down assay. Our results revealed that circ_0004104 was upregulated and miR-100 was downregulated in patients with CAD and ox-LDL-induced VECs. Ox-LDL could inhibit the proliferation and promote the apoptosis and inflammation of VECs to induce VEC injury. However, silenced circ_0004104 could alleviate VEC injury induced by ox-LDL. Moreover, we found that circ_0004104 could sponge miR-100 and a miR-100 inhibitor could reverse the inhibition effect of circ_0004104 knockdown on ox-LDL-induced VEC injury. In addition, TNFAIP8 was a target of miR-100, and miR-100 alleviated ox-LDL-induced VEC injury by targeting TNFAIP8. Our data suggested that circ_0004104 promoted ox-LDL-induced VEC injury by the miR-100/TNFAIP8 axis, indicating that circ_0004104 might be a potential biomarker for CAD treatment.

Long noncoding RNA DLEU2 drives the malignant behaviors of thyroid cancer through mediating the miR-205-5p/TNFAIP8 axis.

ObjectiveConsidering the plight in thyroid cancer therapy, we aimed to find novel therapeutic targets from a molecular perspective.MethodsQuantitative real-time PCR (qRT-PCR) and Western blot assay were carried out to determine RNA and protein expression. Cell counting kit-8 (CCK8) assay, flow cytometry, transwell migration assay and aerobic glycolysis analysis were performed to analyze cell proliferation, apoptosis, migration and aerobic glycolysis of thyroid cancer cells. MiRcode and Starbase software were used to search the downstream genes of long noncoding RNA (lncRNA) deleted in lymphocytic leukemia 2 (DLEU2) and microRNA-205-5p (miR-205-5p), and the intermolecular combination was confirmed by dual-luciferase reporter assay. The in vivo role of DLEU2 in tumor growth was verified using the murine xenograft model.ResultsDLEU2 and tumor necrosis factor-α-induced protein 8 (TNFAIP8) were highly expressed in thyroid cancer tissues and cell lines. DLEU2 and TNRAIP8 promoted the proliferation, migration and aerobic glycolysis and restrained the apoptosis of thyroid cancer cells. DLEU2/miR-205-5p/TNFAIP8 signaling axis was identified in thyroid cancer cells. TNFAIP8 overexpression largely rescued the malignant phenotypes in DLEU2-silenced thyroid cancer cells. DLEU2 positively regulated TNFAIP8 expression by acting as miR-205-5p sponge in thyroid cancer cells. DLEU2 silencing blocked the growth of xenograft tumors in vivo.ConclusionlncRNA DLEU2 exerted a pro-tumor role to promote proliferation, migration and aerobic glycolysis while repressing the apoptosis of thyroid cancer cells via miR-205-5p/TNFAIP8 axis.

RETRACTED ARTICLE: MicroRNA-205-5p inhibits skin cancer cell proliferation and increase drug sensitivity by targeting TNFAIP8

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a member of the TIPE/TNFAIP8 family which regulates tumor growth and survival. Our goal is to delineate the detailed oncogenic role of TNFAIP8 in skin cancer development and progression. Here we demonstrated that higher expression of TNFAIP8 is associated with basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma development in patient tissues. Induction of TNFAIP8 expression by TNFα or by ectopic expression of TNFAIP8 in SCC or melanoma cell lines resulted in increased cell growth/proliferation. Conversely, silencing of TNFAIP8 decreased cell survival/cell migration in skin cancer cells. We also showed that miR-205-5p targets the 3′UTR of TNFAIP8 and inhibits TNFAIP8 expression. Moreover, miR-205-5p downregulates TNFAIP8 mediated cellular autophagy, increased sensitivity towards the B-RAFV600E mutant kinase inhibitor vemurafenib, and induced cell apoptosis in melanoma cells. Collectively our data indicate that miR-205-5p acts as a tumor suppressor in skin cancer by targeting TNFAIP8.

Proteomic Analysis of Plasma sEVs Reveals That TNFAIP8 Is a New Biomarker of Cell Proliferation in Diabetic Retinopathy.

Small extracellular vesicles (sEVs) derived from the plasma have been increasingly recognized as important vehicles of intercellular communication and potential sources of new biomarkers for multiple diseases. In this study, proteomic profiles of plasma sEVs from normal subjects and diabetic patients with or without diabetic retinopathy (DR) were systematically compared using iTRAQ-based quantitative proteomics. Among a total of 901 identified proteins in plasma sEVs (false discovery rate (FDR) < 1%), 90 proteins were found to have significantly changed levels in DR. Based on the findings from the proteomic analysis, the role of tumor necrosis factor-α-induced protein 8 (TNFAIP8) in promoting human retinal microvascular endothelial cell (HRMEC) proliferation was investigated. The enzyme-linked immunosorbent assay (ELISA) showed that TNFAIP8 levels in plasma sEVs and vitreous are elevated in DR, whereas not statistically different in large EVs (lEVs) and plasma. In addition, in vitro experiments demonstrated that 4-hydroxynonenal (4-HNE) increased the expression of TNFAIP8 in HRMECs. TNFAIP8 significantly increased HRMECs cell viability and promote cell migration and tube formation, and the depletion of TNFAIP8 impaired HRMEC proliferation. We demonstrated that TNFAIP8 in plasma sEVs could be used as a potential biomarker of DR. Functional studies suggested that TNFAIP8 might be an important mediator of angiogenesis in DR.

Expression of TIPE family members in human colorectal cancer.

The tumor necrosis factor α-induced protein 8 (TNFAIP8)-like (TIPE) protein family comprises four members, namely TNFAIP8, TIPE1, TIPE2 and TIPE3, which are involved in multiple processes in cancer. The current study aimed to investigate the expression patterns and potential clinical roles of the TIPE family members in human colorectal cancer (CRC). Paired tumor and adjacent tissue samples were collected from 49 patients with CRC, and the relative mRNA expression levels of the TIPE family members in these samples were evaluated by using reverse transcription-quantitative PCR, and the protein levels in five randomly selected pairs of tumor and adjacent tissue samples were detected by western blot analysis. The mRNA expression levels of the TIPE family members were significantly downregulated in CRC tumor tissues compared with those in the adjacent tissues; however, within each sample, TNFAIP8 and TIPE3 protein levels were only partially consistent with their mRNA levels. In addition, the mRNA expression levels between each pair of TIPE family members exhibited a positive linear relationship, and TIPE2 mRNA levels exhibited strong linear associations with those of TNFAIP8 and TIPE1. TNFAIP8 mRNA expression levels in tumor tissues were significantly associated with the tumor differentiation grade, and TIPE2 mRNA expression levels in tumor tissues were significantly associated with sex. TIPE1 and TIPE3 mRNA expression levels in tumor tissues exhibited no associations with patient clinicopathological characteristics. In addition, the mRNA expression patterns of the TIPE family members were analyzed using data from The Cancer Genome Atlas data set, and the results also demonstrated that TNFAIP8, TIPE2 and TIPE3 mRNA levels were downregulated in patients with colon adenocarcinoma compared with those in normal controls. These results provided evidence that the four members of the TIPE family may affect each other to mediate the carcinogenesis of CRC, and that TIPE2 may serve an important role in CRC.

TNFAIP8 drives metabolic reprogramming to promote prostate cancer cell proliferation

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a member of TIPE/TNFAIP8 family, has been involved in the development and progression of various human cancers. We hypothesized that TNFAIP8 promotes prostate cancer (PCa) progression via regulation of oxidative phosphorylation (OXPHOS) and glycolysis. Ectopic expression of TNFAIP8 increased PCa cell proliferation/migration/spheroid formation by enhancing cell metabolic activities. Mechanistically, TNFAIP8 activated the PI3K-AKT pathway and up-regulated PCa cell survival. TNFAIP8 was also found to regulate the expression of glucose metabolizing enzymes, enhancing glucose consumption, and endogenous ATP production. Treatment with a glycolysis inhibitor, 2-deoxyglucose (2-DG), reduced TNFAIP8 mediated glucose consumption, ATP production, spheroid formation, and PCa cell migration. By maintaining mitochondrial membrane potential, TNFAIP8 increased OXPHOS and glycolysis. Moreover, TNFAIP8 modulates the production of glycolytic metabolites in PCa cells. Collectively, our data suggest that TNFAIP8 exerts its oncogenic effects by enhancing glucose metabolism and by facilitating metabolic reprogramming in PCa cells. Therefore, TNFAIP8 may be a biomarker associated with prostate cancer and indicate a potential therapeutic target.

TNFAIP8 influences the motor function in mice after spinal cord injury (SCI) through meditating inflammation dependent on AKT

Spinal cord injury (SCI) is a devastating disease and causes tissue loss and neurologic dysfunction, contributing to high morbidity and disability among human. However, the underlying molecular mechanisms still remain unclear. Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a member of the TNFAIP8/TIPE family, and has been implicated in different diseases associated with inflammation, infection, and immunity. Nevertheless, its effects on SCI have not been well investigated. In our study, we found time course of TNFAIP8 following SCI in mice, along with time-dependent increases of pro-inflammatory cytokines. The in vitro results confirmed the up-regulation of TNFAIP8 induced by lipopolysaccharide (LPS). Subsequently, we found that reducing TNFAIP8 by transfection with its specific siRNA (siTNFAIP8) markedly alleviated cell viability and inflammatory response caused by LPS in mouse microglial BV2 cells. Importantly, LPS-enhanced activation of inhibitor of κBα/nuclear factor-κB (IκBα/NF-κB) and phosphoinositide 3-kinase/serine-threonine kinase (PI3K/AKT) signaling pathways was considerably blunted by siTNFAIP8. Intriguingly, our results further showed that siTNFAIP8-restrained inflammation and IκBα/NF-κB in LPS-stimulated BV2 cells were almost abolished by the pre-treatment of AKT activator SC-79, demonstrating that TNFAIP8-regulated inflammatory response was largely dependent on AKT activation. Then, the in vivo studies were performed using the wild type (WT) and TNFAIP8-knockout (KO) mice with or without SCI operation. Results showed that TNFAIP8-KO mice exhibited improved neuron injury and locomotor function along with decreased microglial activity. Furthermore, compared with the WT/SCI mice, the expression of pro-inflammatory cytokines in spinal cords was markedly down-regulated by TNFAIP8-deficiency through blocking IκBα/NF-κB and PI3K/AKT signaling pathways. Taken together, these findings elucidated the novel role of TNFAIP8 in regulating SCI via the AKT signaling, and thus TNFAIP8 may be served as a promising therapeutic target for SCI treatment.

TIPE2 inhibits the migration and invasion of endometrial cells by targeting β-catenin to reverse epithelial-mesenchymal transition.

Do changes in tumor necrosis factor-α-induced protein 8 (TNFAIP8)-like 2 (TIPE2) levels in endometrium of patients with adenomyosis alter the proliferation, migration and invasion ability of endometrial cells? TIPE2 expression levels were low in eutopic and ectopic endometrium of adenomyosis patients, and TIPE2 inhibited the migration and invasion of endometrial cells, mainly by targeting β-catenin, to reverse the epithelial-mesenchymal transition (EMT). Adenomyosis is a benign disease, but it has some pathophysiological characteristics similar to the malignant tumor. TIPE2 is a novel negative immune regulatory molecule, and it also participates in the development of malignant tumors. Control endometrium (n = 48 women with non-endometrial diseases) and eutopic/ectopic endometrium from patients with adenomyosis (n = 50), human endometrial cancer cell lines, and primary endometrial cells from the eutopic endometrium of adenomyosis patients were used in the study. The expression level of TIPE2 mRNA and protein in the eutopic/ectopic endometrial tissues of adenomyosis patients and control endometrium was determined by quantitative RT-PCR (qRT-PCR), western blot and immunohistochemistry. The effects of TIPE2 overexpression and knockdown on the proliferation, migration and invasion of endometrial cell lines and primary adenomyotic endometrial cells were determined using a cell counting kit-8, 5-ethynyl-2'-deoxyuridine assay, colony-forming assay, transwell migration assay and matrigel invasion assay. The expression of EMT-related markers and signal molecules was detected by western blot. The interaction between TIPE2 and β-catenin was detected by co-immunoprecipitation and laser confocal microscopy. The mRNA and protein expression levels of TIPE2 in the eutopic and ectopic endometrial tissues of adenomyosis patients were significantly downregulated compared with the control endometrium (P˂0.01). TIPE2 could bind to β-catenin and inhibit the nuclear translocation of β-catenin, downregulate the expression of stromal cell markers, upregulate the expression of glandular epithelial cell markers, decrease the occurrence of epithelial-mesenchymal transition (EMT) and suppress the migration and invasion of endometrial cells (P˂0.01). N/A. In this study, the experiments were performed only in eutopic and ectopic endometrial tissues, endometrial cancer cell lines and primary adenomyotic endometrial cells. A mouse model of adenomyosis will be constructed to detect the effects of TIPE2 in vivo. These results suggest that TIPE2 is involved in the development of adenomyosis, which provides a potential new diagnostic and therapeutic strategy for the treatment of adenomyosis. This present study was supported by grants from the National Natural Science Foundation of China (81471437, 81771554), Natural Science Foundation of Shandong (ZR2018MH013), Science and technology development plan provided by Health and Family Planning Committee in Shandong (2014-25). The authors declare that they have no conflicts of interest.

MiR-379 relieves myocardial injury after acute myocardial infarction by regulating tumor necrosis factor-α-induced protein 8.

Acute myocardial infarction (AMI) is the myocardial avascular necrosis syndrome caused by coronary atherosclerotic plaque rupture, thrombosis or coronary artery occlusion. Therefore, it is of great significance to find new targets for the treatment of myocardial infarction. The purpose of this study was to investigate the effect of microRNA-379 (miR-379) on AMI and its mechanism. MiR-379 mimic was used to transfect H9c2 cells and we determined the protective effect of miR-379 on H9c2 by detecting the level of apoptosis. TargetScan software was used to detect miR-379's downstream targets. We constructed siRNA to analyze the effect of miR-379's downstream targets on H9c2 cells. In addition, we used miR-379 agomir to inject the tail vein of AMI rats to verify the effect of miR-379 on rat cardiomyocytes. TargetScan detected that miR-379 and Tumor necrosis factor-α-induced protein 8 (TNFAIP8) may have binding sites and the dual luciferase reporter assay found that miR-379 binds to TNFAIP8 and inhibits its activity. MiR-379 mimic was found to reduce the expression of caspase3 and caspase9 in H9c2 cells and thereby reduce H<inf>2</inf>O<inf>2</inf>-induced cell damage. Inhibition of TNFAIP8 also significantly reduced apoptosis level and inhibited the NF-κB signaling pathway in H9c2 cells. Finally, miR-379 agomir was used to inject the tail vein of AMI rats and verified the protective effect of miR-379 in the heart in vivo. MiR-379 has a binding site with TNFAIP8 and can inhibit its activity by binding to TNFAIP8 mRNA. SiRNA-TNFAIP8 can inhibit the NF-κB signaling pathway and protect myocardial cells from AMI-induced myocardial damage by reducing the apoptosis level of myocardial cells.

TNFAIP8 regulates autophagy, cell steatosis, and promotes hepatocellular carcinoma cell proliferation

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) expression has been linked to tumor progression in various cancer types, but the detailed mechanisms of TNFAIP8 are not fully elucidated. Here we define the role of TNFAIP8 in early events associated with development of hepatocellular carcinoma (HCC). Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins. TNFAIP8 also exhibited binding with fatty acids and modulated expression of lipid/fatty-acid metabolizing enzymes. Chronic feeding of mice with alcohol increased hepatic levels of TNFAIP8, autophagy, and steatosis but not in high-fat-fed obese mice. Similarly, higher TNFAIP8 expression was associated with steatotic livers of human patients with a history of alcohol use but not in steatotic patients with no history of alcohol use. Our data indicate a novel role of TNFAIP8 in modulation of drug resistance, autophagy, and hepatic steatosis, all key early events in HCC progression.

TNFAIP8: Inflammation, Immunity and Human Diseases

Tumor necrosis factor (TNF)-alpha-induced protein 8 (TNFAIP8 /TIPE) family proteins are known to be involved in maintaining immune homeostasis. The TIPE family contains four members: tumor necrosis factor-α-induced protein 8 (TNFAIP8), TNFAIP8 like 1 (TIPE1), TNFAIP8 like 2 (TIPE2), and TNFAIP8 like 3 (TIPE3). Here we review the latest roles and associations of a founding member of TIPE family protein - TNFAIP8 in cellular function/signaling, inflammation, and immunity related human diseases.

Loss of TIPE2 Has Opposing Effects on the Pathogenesis of Autoimmune Diseases.

Autoimmune diseases are a physiological state wherein immune responses are directed against and damage the body's own tissues. Cytokines secreted by infiltrated inflammatory cells contribute to the pathogenesis of autoimmune diseases. TIPE2, one of the four family members of Tumor necrosis factor-α induced protein-8 (TNFAIP8), is a negative regulator of innate and adaptive immunity and plays essential roles in the maintenance of immune tolerance. However, studies on the role of TIPE2 during the development of autoimmune diseases have generated contradictory results. In the current study, we sought to determine the role of TIPE2 during the development of IMQ-induced psoriasis and Experimental Autoimmune Uveitis (EAU) in mice. Our study revealed that, while TIPE2-deficiency alleviates psoriasis, it exacerbates the development of EAU. Further studies demonstrated that, although TIPE2-deficient T cells produced more IL-17A, they do not migrate efficiently to the local inflammatory site, i.e., the skin. This in turn led to the decreased IL-17A production in the skin and consequently reduced the severity of psoriasis in TIPE2-deficient mice. However, although TIPE2-deficient T cells still produced more IL-17A in EAU model, they migrate into the inflamed eye as efficient as TIPE2-sufficient T cells, and consequently exacerbates the development of EAU in TIPE2-deficient mice. Taken together, these results indicate that TIPE2 may either promote or suppress autoimmunity depending on the specific inflammatory microenvironment in different types of autoimmune diseases.

TNFAIP8 promotes cisplatin resistance in cervical carcinoma cells by inhibiting cellular apoptosis.

Cervical cancer is the second most prevalent malignant tumor in women worldwide. Failure of successful treatment is most prevalent in patients with the metastatic disease and the chemotherapy refractory disease. Tumor necrosis factor α-induced protein 8 (TNFAIP8) serves as an anti-apoptotic and pro-oncogenic protein, and is associated with cancer progression and poor prognosis in a number of different cancer types. However, the physiological and pathophysiological roles of TNFAIP8 in cervical carcinogenesis and development remain poorly understood. In the present study, it was demonstrated that TNFAIP8 protein expression levels were significantly increased in cervical cancer tissues compared with the non-tumor adjacent tissues using immunohistochemistry. Additionally, it was demonstrated that TNFAIP8 overexpression is associated with cisplatin resistance. Furthermore, depletion of TNFAIP8 impaired HeLa cell proliferation and viability in vitro, improved cisplatin sensitivity, and promoted cisplatin-induced cellular apoptosis and death. Subsequent mechanistic analysis demonstrated that TNFAIP8 silencing promoted caspase-8/-3 activation and p38 phosphorylation in HeLa cells treated with cisplatin, whereas apoptosis regulator B-cell lymphoma-2 expression was inhibited with TNFAIP8-silenced HeLa cells following treatment with cisplatin. These data suggested that TNFAIP8 serves as an anti-apoptotic protein against cisplatin-induced cell death, which eventually leads to chemotherapeutic drug-treatment failure. Therefore, the present data suggested that TNFAIP8 may be a promising therapeutic target for the treatment of cervical cancer.

Oncogenic Role of Tumor Necrosis Factor α-Induced Protein 8 (TNFAIP8).

Tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8) is a founding member of the TIPE family, which also includes TNFAIP8-like 1 (TIPE1), TNFAIP8-like 2 (TIPE2), and TNFAIP8-like 3 (TIPE3) proteins. Expression of TNFAIP8 is strongly associated with the development of various cancers including cancer of the prostate, liver, lung, breast, colon, esophagus, ovary, cervix, pancreas, and others. In human cancers, TNFAIP8 promotes cell proliferation, invasion, metastasis, drug resistance, autophagy, and tumorigenesis by inhibition of cell apoptosis. In order to better understand the molecular aspects, biological functions, and potential roles of TNFAIP8 in carcinogenesis, in this review, we focused on the expression, regulation, structural aspects, modifications/interactions, and oncogenic role of TNFAIP8 proteins in human cancers.