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Objective: TNFAIP8 and TIPE2 belong to TNFa-induced protein 8 (TNFAIP8/TIPE) family. They control apoptosis and direct leukocyte migration. Nucleus pulposus cell loss is a hallmark of intervertebral disc degeneration in response to injury, and inflammation may cause pain. Here, we examined the effects of TNFAIP8/TIPE2 deficiency on the intervertebral discs in mice with these genes deleted. Design: Tail intervertebral discs in Tnfaip8 or Tipe2 single and double knockout mice (Tnfaip8−/− , Tipe2−/− , and Tnfaip8/Tipe2 dko), and wild-type controls were injured. The spine motion segments were stained with safranin O to reveal proteoglycans. Macrophages were identified by immunostaining, and selected inflammatory marker and collagen gene expression was examined by Real Time PCR. Results: The injured tail intervertebral discs of Tnfaip−/− , Tipe2−/− , and Tnfaip8/Tipe2 dko mice all displayed higher levels of proteoglycans than wild-type controls. Fewer macrophages were found in the injured intervertebral discs of Tipe2−/− and Tnfaip8/Tipe2 dko mice than wild type. Il6, Adam8, and Col1 gene expression was downregulated in the injured intervertebral discs of Tnfip8/Tipe2 dko mice. Conclusions: TNFAIP8 and TIPE2 loss of function ameliorated proteoglycan loss and inflammation in the injured intervertebral discs. They may serve as molecular targets to preserve disc structure and reduce inflammation. [ABSTRACT FROM AUTHOR]

The multiple roles of the tumor necrosis factor (TNF)-α-inducible protein 8 (TNFAIP8), also named TIPE family of proteins have been shown in tumor and inflammation progression and regulation of cellular autophagy and apoptosis. In this review, we found that the TIPE family showed highly homologous sequences and conserved functional domains, such as the death effector domain (DED)-like domain but displayed different roles and mechanisms in different biological activities. For example, while TIPE is primarily associated with tumor progression and antitumor drug resistance, TIPE1 suppresses tumor progression in most instances. TIPE2 has multiple roles in tumor progression regulation, and antitumor drug resistance. Moreover, TIPE2 was also involved in inflammatory response regulation, tumor typing, and staging. A few studies reported that TIPE3 was engaged in tumor development by activating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. The structure, function, and mechanism of the TIPE family in cancer and inflammation have been summarized in this review. This might serve as a reference for further research on the TIPE family and shed new light on the crosstalk among antitumor responses, inflammation, and immunology. [ABSTRACT FROM AUTHOR]

Background and Aim: Neuroinflammation plays an early and prominent role in the pathology of Parkinson disease. Tumor necrosis factor alpha induced protein-8 like-2 (TIPE2) is a relatively new subtype of tumor necrosis factor which may play a role in pathogenesis of Parkinson disease. Our aim was to evaluate the role of serum level of TIPE2 as a risk factor for Parkinson disease and as a serological biomarker of disease severity. Methods: Forty-seven patients diagnosed as idiopathic PD according to diagnostic criteria of the UK Parkinson Disease Society Brain Bank, and 47 healthy individuals were enrolled. All patients were on medical treatment of PD and were evaluated by Unified Parkinson's disease Rating Scale (UPDRS), and Modified Hoehn and Yahr staging scale(HY). Cognitive function was assessed using Montreal Cognitive Assessment Scale (MOCA). TIPE2 serum level was measured in all participants. Results: PD patients had significantly higher levels of TIPE2 (P-value <0.001). Also, PD patients with cognitive impairment had significantly higher levels of TIPE2 (P-value= 0.039). TIPE2 level was positively correlated with score of modified HY staging (p-value o.oo1). Also, TIPE2 level was positively correlated with bradykinesia, total motor sub scores of UPDRS and total score of UPDRS (p-value 0.009, 0.019, 0.027 respectively). There was a significant negative correlation between TIPE2 and the scores of executives and visuospatial functions, attention, abstraction and total score of MoCA. Conclusions: TIPE2 serum levels in PD patients are higher than its serum level in healthy controls. Such high level of TIPE2 has a considerable impact on disease severity. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-alpha (TNF-α)-induced protein 8 (TNFAIP8/TIPE) family, including TNFAIP8 (TIPE), TNFAIP8 like-protein 1 (TNFAIP8L1/TIPE1), TNFAIP8 like-protein 2 (TNFAIP8L2/TIPE2), and TNFAIP8 like-protein 3 (TNFAIP8L3/TIPE3), plays a vital role in regulating inflammatory responses, immune homeostasis, and cancer development. Over the last decade, studies have shown that TIPE2 protein is differentially expressed in diverse cells and tissues. The dysregulation of TIPE2 protein can lead to dysregulation of inflammatory responses and immune homeostasis, and change the basic characteristics of cancers. In consideration of the immeasurable values of TIPE2 in diagnosis, treatment, and prognosis of various human diseases, this review will focus on the expression pattern, structure, and regulatory roles of TIPE2 in inflammation, immunity, and cancers. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-a induced protein 8 like 2 (TIPE2) is one of the newly discovered negative regulators for body's immune balance. The present study aimed to investigate the effect of TIPE2 gene-modified human amniotic mesenchymal stem cells (hAD-MSCs) on immune tolerance. In this study, the TIPE2 over-expressed and the non-transfected hAD-MSCs were severally co-cultured with injured cardiomyocytes. Cell cycle and apoptosis were detected by flow cytometry. Cell viability was measured by MTT, and expressions of immune-related factors were detected by qRT-PCR and western blot. When compared with the empty vector-transfected hAD-MSCs, the TIPE2-overexpression hAD-MSCs co-cultured with injured cardiomyocytes show accelerated cell viability and declined apoptosis. After TIPE2 over-expression, the mRNA and protein levels of p38, extracellular signalregulated kinases (ERK) and interferon-γ (INF-γ) notably decreased, whereas those of transforming growth factor-ß (TGF-ß) and interleukin-10 (IL-10) increased in a converse trend. This study suggested that TIPE2 may enhance the cellular immune tolerance in co-culture systems of hAD-MSCs and injured cardiomyocyte, providing a theoretical basis for the allogeneic heart transplantation. [ABSTRACT FROM AUTHOR]

Asthma is a chronic reversible airway disease, results from genetic - environmental interaction. Inflammatory processes may aggravate the severity of asthma and stimulate the airway remodeling. The aim of the current study is to evaluate the association between the negative inflammatory regulators; tumor necrosis factor α induced protein 8 like 2 (TIPE2) and Programmed cell death-1 (PD-1 with bronchial asthma in Iraqi population. blood samples are collected from 100 patients diagnosed with bronchial asthma (59 females and 41 males), their ages ranged between 2 to 61 years and 30 healthy individuals (14 females and 16 males) with the same age range. DNA extracted and then subjected to real time PCR for detection of gene expression. TIPE2 and PD-1 have low folding change of genes expression in asthmatic patients (0.01 and 0.10 respectively) compared to healthy control (1.00) which is reflect the significant differences (p<0.05). TIPE2 and PD-1 that have down expression (folding mean) in patients with familial asthma and the noted expression of these genes are clearly appeared in females (0.02 and 0.14 respectively). Also the lowest level of PD-1 gene expression was seen in unclassified group and then in moderate persist asthma (0.02, 0.11 respectively). While the lowest level of TIPE2 gene expression was seen in sever persist asthma, then moderate persist asthma and unclassified group (0.005, 0.006 and 0.008 respectively) .PD1 not affected by treatment but TIPE2 affected and increased. There are a significant negative correlation for each one of TIPE2, PD-1 with asthma infection. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The role of tumor necrosis factor α (TNF-α) induced protein 8-like-2 (TIPE2) in Pseudomonas aeruginosa (PA) keratitis was explored.Methods: Eight-week-old TIPE2 knockout (TIPE2-/-) C57BL/6 mice and their wild-type (WT) littermates were used. Corneal disease was graded at 1, 2, and 3 days postinfection, and slit lamp, clinical score, histopathology, and immunostaining were performed in the infected corneas. The corneas were harvested, and messenger ribonucleic acid (mRNA) levels of TNF-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6) were tested. Enzyme-linked immunosorbent assay (ELISA) determined the protein levels, and nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) signaling molecules were tested by Western blot. In vitro human corneal epithelial cells (HCECs) were used to determine the relationship between TIPE2 and TAK1. The HCECs were treated with TIPE2 short hairpin ribonucleic acid (shRNA) and lipopolysaccharide (LPS) to test the NF-κB signaling molecules by Western blot.Results: Pseudomonas aeruginosa infection induced a decreased expression of TIPE2 in mouse corneas 2 days postinfection. Compared with the control group, TIPE2-deficient mice were susceptible to infection with PA and showed increased corneal inflammation. Reduced NF-κB signaling and inflammatory cell infiltration were required in the TIPE2-mediated immune modulation.Conclusions: TIPE2 promoted host resistance to PA infection by suppressing corneal inflammation via regulating TAK1 signaling negatively and inhibiting the infiltration of inflammatory cells. [ABSTRACT FROM AUTHOR]

Abstract Dendritic cells (DCs) are professional antigen-presenting cells. The main function of DCs is to process antigen and present it to the T cells to induce T cell immunity. In addition to their function as potent stimulators of adaptive immunity, DCs are also crucial for maintaining immunological tolerance through the induction of peripheral regulatory T cells. Tumor necrosis factor-α-induced protein 8-2 (Tumor necrosis factor-α induced protein-8-like 2, TNFAIP8L2 or TIPE2) was expressed primarily by immune cells and maintains immune tolerance through the negative regulation of innate and adaptive immune responses. Previous studies indicate that TIPE2 in DCs may inhibit the innate immune response to RNA. However, the role of TIPE2 in DCs in the induction of peripheral tolerance remains unknown. Our current study showed that Tipe2-deficient DCs are more immature under homeostatic condition and consequently promote the induction of peripheral Tregs in the gut mucosa. Mechanistic studies revealed that TIPE2 promotes the expression of DC maturation markers CD80 and CD86 through the activation of PI3K-PKCδ-MAPK signaling pathway during the differentiation of DCs. Taken together, these results indicate that, in addition to acting as a negative regulator of pathogen-induced immune response, TIPE2 in DCs is also capable of promoting immune response under homeostatic condition through the suppression of peripheral tolerance. Highlights • Tipe2-deficient DCs are more immature under homeostatic condition. • Tipe2 acts as an activator of PI3K-PDK1-PKCδ-MAPK signaling pathway during the differentiation of DCs. • Tipe2-deficiency in DCs promotes the induction of pTregs in the gut mucosa. [ABSTRACT FROM AUTHOR]

Different immune-mediated mechanisms involved in the pathogenesis of Parkinson disease (PD) as a neurodegenerative and inflammatory disease. According to our knowledge, there is no report evaluating Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2), a cytokine maintaining immune homeostasis, in PD. We analyzed the correlation of the serum levels and circulatory gene expression of TIPE2 with severity of PD. In this case-control study, 43 patients with PD and 40 healthy subjects were enrolled. The diagnosis of PD was performed byclinical diagnostic criteria of the UK Parkinson’s Disease Society Brain Bank. The severity of PD was evaluated by modified Hoehn and Yahr (H and Y) scale. Serum levels and gene expression of TIPE2 were assessed by Elisa and real time PCR, respectively. The mean serum levels and gene expression of TIPE2 in patients with PD did not have significant difference compared to healthy subjects. Linear multiple regression analysis showed that increased serum levels of TIPE2 are positively related to age and severity of PD (P ≤ 0.0001). In addition, the gene expression of TIPE2 was found to be associated with age (P < 0.0001). Our study showed that the serum levels of TIPE2 and its gene expression might be important prognostic biomarkers of PD. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) can be divided into thymus-derived Treg (tTregs) and peripheral induced Tregs (pTregs) in vivo according to their origins and are essential for the maintenance of immune hemostasis and immune tolerance. Tumor necrosis factor-α-induced protein 8 like 2 (TIPE2) is expressed primarily by immune cells and is a negative regulator of the innate and adaptive immune response. Previous studies indicate that TIPE2 is required for the expression of Treg signature genes and promotes leading-edge formation in neutrophils through cytoskeleton remodeling. In the current study, we showed that TIPE2 deficient mice accumulate more Treg cells in the thymus. Further studies revealed that TIPE2 deficiency doesn't affect the development and apoptosis of tTregs. Instead, TIPE2 promotes the chemotaxis of tTregs in vitro , which may account for the accumulation of Tregs in the thymus of TIPE2 deficient mice. Mechanistic study revealed that TIPE2 promotes the polarization of pAKT and F-actin in tTregs undergoing directed migration. Taken together, these results demonstrated that TIPE2 enhances the cytoskeleton remodeling and promotes the thymus egress of tTregs, which may play an important role in the maintenance of self-tolerance. [ABSTRACT FROM AUTHOR]

Purpose: Endothelial dysfunction accounts for 50% of total corneal transplantation failures, suggesting that corneal endothelial damage is the leading cause of graft failure. Tumor necrosis factor-α (TNF-α) is known to contribute to the negative regulation of corneal transplantation, but how it does so remains unclear. Here, we report a regulatory loop involving TNF-α, TNF-α-induced protein 8 like 2 (TNFAIP8L2 or TIPE2), and apoptosis during corneal graft rejection.Methods: We established mice models of penetrating keratoplasty to verify whether the quantification of TNF-α in allogeneic corneas is enhanced through ELISA assay and immunofluorescence staining. In cornea tissues, we obtained corneal endothelium and measured apoptosis of the removed cells. Meanwhile, quantitative real-time PCR and Western blotting were used to detect the mRNA and protein expression of TIPE2. In human corneal endothelial cells, we verified the conclusions through some experiments. By specifically knocking down TIPE2, we detected the importance of TIPE2 in TNF-α-triggered apoptosis.Results: In mice models, TNF-α was higher in the cornea and aqueous humor in allograft group and TNF-α elevation increased the apoptosis of the corneal endothelium. In addition, high levels of TIPE2 were found in allograft rejection models following TNF-α elevation. In human corneal endothelial cells (HCECs), TNF-α clearly augments TIPE2 expression and promotes cell apoptosis through upregulating TIPE2 transcription. Knocking down markedly decreased cell apoptosis.Conclusions: Our study identifies the molecular mechanisms underlying the interplay of TNF-α, TIPE2, and apoptosis during allograft rejection, and it suggests that both TNF-α and TIPE2 might be potential targets for the successfully grafted corneal endothelium. [ABSTRACT FROM AUTHOR]

Background: Esophageal carcinoma is the eighth prevalent malignancy and ranks the sixth in carcinoma-related death worldwide. Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) has been identified as a tumor suppressor in multiple carcinomas. However, its roles and molecular mechanisms underlying esophageal carcinoma progression are still undefined till now.Methods: RT-qPCR assay was employed to detect the expression of TIPE2 mRNA. TIPE2 protein expression was measured by using western blot assay. Ad-V and Ad-TIPE2 adenoviruses were constructed to overexpress TIPE2. The effects of TIPE2 overexpression on cell proliferation, invasion and apoptosis were assessed by MTT and Edu incorporation assays, transwell invasion assay and flow cytometry analysis, respectively. The effect of TIPE2 overexpression on xenograft tumor growth was determined by measuring tumor volume and weight, together with immunohistochemistry assay. The effect of TIPE2 overexpression on the Wnt/β-catenin signaling pathway was evaluated by detecting the protein levels of β-catenin, c-Myc and cyclinD1 in EC9076 cells and xenograft tumors of esophageal carcinoma.Results: TIPE2 expression was downregulated in esophageal carcinoma tissues and cells. Adenovirus-mediated TIPE2 overexpression suppressed cell proliferation and invasion, and induced apoptosis in esophageal carcinoma cells. Enforced expression of TIPE2 inhibited tumor growth in vivo, as evidenced by the reduced tumor volume, tumor weight and proliferating cell nuclear antigen expression. Overexpression of TIPE2 inhibited the Wnt/β-catenin signaling pathway in esophageal carcinoma in vitro and in vivo.Conclusions: These results suggest that TIPE2 suppressed progression and tumorigenesis of esophageal carcinoma via inhibition of the Wnt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

• Abnormal TIPE2 expression in immune-related diseases. • TIPE2 is involved in innate and adaptive immunity. • TIPE2 regulates immune response through a variety of pathways. 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. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the underlying mechanism of toll‑like receptor (TLR) agonist polyinosinic:polycytidylic acid (Poly I:C)‑induced apoptosis in THP‑1 cells following silencing the expression of tumor necrosis factor α‑induced protein 8‑like 2 (TIPE2). THP‑1 cells were incubated with different concentrations of the TLR agonist. Following incubation, reverse transcription‑quantitative polymerase chain reaction was performed to quantify the mRNA expression of TIPE2. Lentiviral technology was used to silence the expression of TIPE2. MTT assay was performed to assess cell proliferation, Annexin V/PI double staining was used to evaluate the apoptosis and western blotting was used to determine the expression levels of caspase‑8 following TIPE2 silencing. The TLRs agonist Poly I:C increased the expression level of TIPE2. During the incubation, Poly I:C also inhibited the proliferation of THP‑1 cells and induced apoptosis. Following silencing of TIPE2 in THP‑1 cells, the Poly I:C‑induced TIPE2 expression was significantly downregulated. Additionally, the Poly I:C‑induced proliferation inhibition and apoptosis in THP‑1 cells were significantly reduced following silencing of TIPE2. The findings of the western blot analysis indicated that the active form of caspase‑8, p18, was downregulated following silencing of TIPE2. In conclusion, the expression of TIPE2 in THP‑1 cells may be upregulated by Poly I:C, which may also inhibit cell proliferation and induce apoptosis. Following the downregulation of TIPE2 the aforementioned effect of Poly I:C treatment was reversed and may be associated with the reduced activity of caspase‑8 that was observed in the TIPE2 silenced group. [ABSTRACT FROM AUTHOR]

Background: Missed abortion is a common occurrence for otherwise healthy women. Immunological factor is one of the most important reasons. Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) is a novel negative immune regulator related to several human diseases. However, the expression level and clinical significance of TIPE2 in missed abortion remain unclear. Methods: The expression of TIPE2 mRNA and protein in decidua and chorion from 36 missed abortion patients and 36 healthy controls was detected using quantitative real-time PCR, western blot and immunohistochemistry. In addition, serum TNF-α and IL-10 levels were measured using flow cytometry. Serum estradiol and progesterone levels were measured by radioimmunoassay test. The correlations of TIPE2 protein levels with TNF-α, IL-10, estradiol and progesterone were further analyzed. Results: TIPE2 protein levels were significantly lower in decidual tissues of missed abortion patients than those in healthy controls. The patients with missed abortion had significantly higher levels of serum TNF-α, and lower levels of serum IL-10, estradiol and progesterone compared with healthy controls. The TIPE2 protein levels were positively related to serum IL-10 levels. Conclusion: Our data indicate TIPE2 could play important roles in maintaining the maternal-fetal tolerance and decreased TIPE2 expression in the decidua may be related to the development of missed abortion. [ABSTRACT FROM AUTHOR]

Breast cancer is the second leading cause of cancer-related deaths in the female patients which was mainly caused by metastasis. Development of target gene therapy for breast cancer to suppress tumor progress and metastasis will improve the therapeutic options and be of great benefit to the patients. Tumor necrosis factor-alpha-induced protein 8-like 2 is a novel molecule for maintaining immune homeostasis and is involved in cancer development. In the present study, we overexpressed TIPE2 in breast cancer cells to investigate the role of TIPE2 in the development of breast cancer. Our results showed that overexpression of TIPE2 significantly inhibited the proliferation of 4T1 cells in vitro and in vivo. We constructed a non-viral targeted gene therapeutic system by using the minicircle plasmids expressing TIPE2. We found that the growth and metastasis of breast cancer was significantly inhibited by hydrodynamic gene delivery of TIPE2 plasmids in vivo. Mechanistically, TIPE2 increased T and NK cells, and decreased MDSCs. Gene delivery of TIPE2 up-regulated the production of IFN-γ and TNF-α by CD8 + T and NK cells in spleens and tumor microenvironment, and enhanced the cytotoxic activity of CD8 + T and NK cells. Taken together, TIPE2 inhibited breast cancer development and metastasis possibly via promoting CD8 + T and NK cell-mediated antitumor immune responses. Thus, the results indicate that TIPE2 may be a potential therapeutic target for breast cancer therapy. [ABSTRACT FROM AUTHOR]

TIPE2, also known as TNFAIP8L2, a member of the tumor necrosis factoralpha- induced protein-8 (TNFAIP8) family, is known as an inhibitor in inflammation and cancer, and its overexpression induces cell death. We examined the role of TIPE2 with respect to adjuvant arthritis (AA)-associated pathogenesis by analyzing the TIPE2 regulation of death receptor (DR5)-mediated apoptosis in vitro. The results showed that TIPE2 was detected in normal fibroblast-like synoviocytes (FLSs), but scarcely observed in AA-FLSs. Therefore, recombinant MIGR1/TIPE2+/+ and control MIGR1 lentivirus vectors were transfected to AA-FLSs, which were denoted as TIPE2+/+-FLSs and MIGR1-FLSs, respectively. Our results showed that TIPE2+/+-FLSs were highly susceptible to ZF1-mediated apoptosis, and ZF1 was our own purification of an anti-DR5 single chain variable fragment antibody. Under the presence of TIPE2, the expression of DR5 was significantly increased compared with that of the MIGR1-FLS group. In contrast, the level of phosphorylated nuclear factor-kappa B (pNF-κB) was lower in the TIPE2+/+-FLS group treated with ZF1, whereas the activity of caspase was higher. Moreover, the rate of apoptosis in the TIPE2+/+-FLS group, which was pretreated with caspase inhibitor Z-VAD-FMK, was significantly decreased. In contrast, the apoptosis occurrence in the MIGR1-FLS group increased significantly with the pretreatment of the NF-κB inhibitor Bay. These results indicated that TIPE2 increased the apoptosis of AA-FLSs by enhancing DR5 expression levels, thereby promoting the activation of caspase and inhibiting the activation of NF-κB in AA-FLSs. TIPE2 might potentially act as a therapeutic target for rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Background/Aims: We have recently shown that macrophage polarization may alter the pathogenesis and severity of systemic lupus erythematosus (SLE). However, a practical approach to modulate macrophage polarization in vivo is so far not available. In the current study, we aimed to use tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2) to regulate macrophage polarization in vitro and in vivo, and to study the effects on experimental SLE. Methods: We prepared adeno-associated virus carrying TIPE2 (AAV-TIPE2). We induced experimental SLE in mice with an activated lymphocyte-derived DNA (ALD-DNA) method. We examined the effects of TIPE2 overexpression on macrophage polarization in vitro, and in vivo in the SLE model. We also examined the effects of TIPE2 overexpression on the severity of SLE, by serum anti-dsDNA autoantibody, renal pathological changes, and urine protein levels. Results: ALD-DNA induced SLE-like features in mice, manifested by induction of serum anti-dsDNA autoantibody, renal pathological changes, and increases in urine protein levels. TIPE2 overexpression by AAV-TIPE2 induced macrophage polarization to a M2 phenotype, in vitro and in vivo in the SLE mouse model. TIPE2 overexpression significantly decreased SLE severity. Conclusion: TIPE2 alleviates experimental SLE through induction of macrophage polarization to a M2 phenotype, which may be used as a promising therapeutic strategy for treating SLE. © 2016 The Author(s) Published by S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The present study aims to investigate the expression pattern of TIPE2 protein and its clinical significance in human non-small cell lung cancer (NSCLC). We investigated the expression levels of TIPE2 in 96 NSCLC tumor samples by immunohistochemistry and then analyzed its clinical significance. Furthermore, the role of TIPE2 on the biological properties of the NSCLC cell line H1299 and A549 was experimentally tested in vitro and in vivo . We found that the expression level of TIPE2 was significantly higher in normal lung tissues compared with NSCLC tissues ( P < 0.001), and TIPE2 downregulation was significantly correlated with advanced TNM stage ( P = 0.006). TIPE2 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TIPE2 plasmid was performed in H1299 and A549 cells. TIPE2 overexpression inhibited lung cancer cell proliferation, colony formation and cell invasive in vitro , and prevented lung tumor growth in vivo . In addition, TIPE2 transfection reduced the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. Taken together, our results demonstrate that TIPE2 might serve as a tumor suppressor in NSCLC progression. [ABSTRACT FROM AUTHOR]

AIMS: TIPE2 is a novel inflammation regulator, and the role of TIPE2 in colitis-induced colon cancer is not clear. The aim of this study was to test whether TIPE2 inhibits TLR4 pathway in colon cancer patients and to explore potential mechanism of TIPE2 in colon cancer by caspase-8.METHODS: Expression of TIPE2 and TLR4 in human colon cancer tissues and cell line HT-29 was detected by immunohistochemistry or real-time PCR. TIPE2 mRNA was suppressed by siRNA transfection and the transfection efficiency was proved by fluorescence microscopy and real-time PCR. TLR4 pathway was activated by treating the cells with 1 μg/ml LPS for 4 h. Caspase-8 activities were tested by colorimetric assay in four HT-29 cell groups.RESULTS: TIPE2 was expressed in the cytoplasm of colon cancer tissues and HT-29 cells. TIPE2 expression was more pronounced in colon cancer tissues compared to normal controls and it was related with lymph node metastasis and Dukes stage of colon cancer. TIPE2 expression was positively correlated with that of TLR4 in colon cancer (r=0.7354). TIPE2 expression was knocked down successfully by siRNA transfection. Caspase-8 activity was elevated both in TIPE2 knockdown cells and in TLR4 activated cells compared to wild-type cells (P< 0.05). And the caspase-8 activity was further increased in TIPE2 knockdown cells after TLR4 was activated (P < 0.05). CONCLUSION: TIPE2 can inhibit caspase-8 activity in colon cancer cells. TIPE2 can regulate TLR4 inflammatory effect and inhibit further amplification of cascade reaction via caspase-8, which provides one new therapeutic target for clinical treatment schedule. [ABSTRACT FROM AUTHOR]

Background Tumor invasion and metastasis are the major reasons for leading death of patients with hepatocellular carcinoma (HCC). Therefore, to identify molecules that can suppress invasion and metastasis of tumor will provide novel targets for HCC therapies. Tumor necrosis factor (TNF)-alpha-induced protein 8-like 2, TIPE2, is a novel immune negative molecule and an inhibitor of the oncogenic Ras in mice but its function in human is unclear. Our previous research has shown that TIPE2 is downregulated in human primary HCC compared with the paired adjacent non-tumor tissues. Results In present study, we provide evidence that TIPE2 inhibits effectively human hepatocellular carcinoma metastasis. The forced expression of TIPE2 in HCC-derived cell lines markedly inhibits tumor cell growth, migration and invasion in vitro and suppresses growth and metastasis of HCC in vivo. Clinical information from a cohort of 112 patients reveals that loss or reduced expression of TIPE2 in primary HCC tissues is significantly associated with tumor metastasis. Mechanically, TIPE2 inhibits the migration and invasion through targeting Rac1 and then reduces F-actin polymerization and expression of matrix metallopeptidase 9 (MMP9) and urokinase plasminogen activator (uPA). Conclusion Our results indicate that human TIPE2 is endogenous inhibitor of Rac1 in HCC by which it attenuates invasion and metastasis of HCC. The data suggest that TIPE2 will be a new target for HCC therapy. [ABSTRACT FROM AUTHOR]

• Downregulation of TIPE2 inversely correlated with the arthritis progression in the CIA mice. • Gene delivery of TIPE2 prevented the susceptibility and disease severity of CIA. • TIPE2 inhibits the infiltration of macrophages and myeloid-derived suppressor cell (MDSCs) in the joints of the CIA mice. • TIPE2 inhibits proinflammatory cytokines expression in CIA mice through regulating STAT3 and NF-κB. Rheumatoid arthritis (RA) is an autoimmune disease that leads to severe disabilities through the induction of synovitis and subsequent cartilage and bone destruction. The development of a novel therapeutic strategy for suppressing inflammatory responses in RA will be of great benefit to patients. Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) is an important regulator of immune response in various diseases. However, the expression and function of TIPE2 in RA are still unclear. In the present study, the expression of TIPE2 during the development of collagen-induced arthritis (CIA) was determined. Lentivirus (LV) was utilized to deliver a TIPE2 overexpression system into the joints of CIA mice, and this was followed by pathological analysis, immune cell infiltration analysis, and inflammatory cytokine detection. TIPE2 was downregulated in CIA mice, which was inversely correlated with arthritis progression. The ectopic expression of TIPE2 from gene delivery prevented susceptibility and disease severity by inhibiting the infiltration of macrophages and myeloid-derived suppressor cells (MDSCs) in the joints of CIA mice. Furthermore, lower expression of proinflammatory cytokines was observed in LV-TIPE2-injected CIA mice, which was in part associated with the activation of STAT3 and NF-κB signaling pathways in the cartilage cells. These data support the suppressive function of TIPE2 in autoimmune diseases and identify the gene delivery of TIPE2 as an important therapeutic agent for the treatment of RA and perhaps other autoimmune diseases. [ABSTRACT FROM AUTHOR]

The tumor necrosis factor-α-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-α-induced protein 8 (TIPE/TNFAIP8), tumor necrosis factor-α-induced protein 8-like 1 (TIPE1/TNFAIP8L1), tumor necrosis factor-α-induced protein 8-like 2 (TIPE2/TNFAIP8L2), and tumor necrosis factor-α-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. [ABSTRACT FROM AUTHOR]

Background: Tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2 or TNFAIP8L2) is a newly described negative immune regulator and is closely associated with various tumors. However, the expression and roles of TIPE2 in PTC is unknown. Results: In the present study, TIPE2 upregulation in PTC tissues was found to be negatively associated with tumor size, capsule infiltration, peripheral infiltration and tumor T stage, which could be used to predict tumor invasiveness. TIPE2 overexpression significantly suppressed the viability, proliferation, migration and invasion of PTC cells. Moreover, TIPE2 suppressed tumor invasiveness by inhibiting Rac1, leading to decreased expression of uPA and MMP9. Conclusions: These results indicate that TIPE2 is a potential biomarker for predicting tumor aggressiveness and suppresses tumor invasiveness in a Rac1-dependent manner. [ABSTRACT FROM AUTHOR]