Search

Recent studies have uncovered that TIPE2 is involved in the development of cancer. However, less research has been conducted on the role of TIPE2 in melanoma. Our study aims to elucidate the mechanism of action of TIPE2 in the development of melanoma. We examined TIPE2 expression in paracarcinoma tissue and melanoma tissues and found that TIPE2 expression was downregulated in melanoma tissue compared with paracarcinoma tissue. Overexpression of TIPE2 significantly inhibited the proliferation of melanoma cells in vitro and even inhibited tumor formation in vivo. The CCK8 assay results indicated that TIPE2 overexpression suppressed the proliferation of melanoma cells. The colony-forming ability and wound healing ability of TIPE2-overexpressing melanoma cells were significantly reduced compared with those of control cells. Moreover, immunohistochemistry experiments using a nude mouse tumor model showed consistent results. TIPE2 inhibited the phosphorylation of MEK and ERK. In summary, TIPE2 suppresses the proliferation and migration of melanoma cells by affecting proliferation-related factors and possibly by regulating the MEK/ERK pathway. TIPE2 could be used to inhibit melanoma growth and is a potential drug target for future drug development. [ABSTRACT FROM AUTHOR]

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]

Abstract Recent studies have uncovered that TIPE2 is involved in the development of cancer. However, less research has been conducted on the role of TIPE2 in melanoma. Our study aims to elucidate the mechanism of action of TIPE2 in the development of melanoma. We examined TIPE2 expression in paracarcinoma tissue and melanoma tissues and found that TIPE2 expression was downregulated in melanoma tissue compared with paracarcinoma tissue. Overexpression of TIPE2 significantly inhibited the proliferation of melanoma cells in vitro and even inhibited tumor formation in vivo. The CCK8 assay results indicated that TIPE2 overexpression suppressed the proliferation of melanoma cells. The colony-forming ability and wound healing ability of TIPE2-overexpressing melanoma cells were significantly reduced compared with those of control cells. Moreover, immunohistochemistry experiments using a nude mouse tumor model showed consistent results. TIPE2 inhibited the phosphorylation of MEK and ERK. In summary, TIPE2 suppresses the proliferation and migration of melanoma cells by affecting proliferation-related factors and possibly by regulating the MEK/ERK pathway. TIPE2 could be used to inhibit melanoma growth and is a potential drug target for future drug development.

Epithelial ovarian cancer is the deadliest gynecologic malignancy, characterized by high metastasis. Transforming growth factor‐β1 (TGF‐β1) drives epithelial‐ mesenchymal transformation (EMT), a key process in tumor metastasis. Tumor necrosis factor‐α‐induced protein 8 (TNFAIP8)‐like 2 (TIPE2) acts as a negative regulator of innate and adaptive immunity and involves in various cancers. However, its relationship with TGF‐β1 in ovarian cancer and its role in reversing TGF‐β1‐induced EMT remain unclear. This study examined TIPE2 mRNA and protein expression using quantitative RT‐PCR (qRT‐PCR), western blot and immunohistochemistry. The effects of TIPE2 overexpression and knockdown on the proliferation, migration and invasion of epithelial ovarian cancer cells were assessed through 5‐ethynyl‐2‐deoxyuridine, colony‐forming, transwell migration and invasion assays. The relationship between TIPE2 and TGF‐β1 was investigated using qRT‐PCR and enzyme‐linked immunosorbent assay, while the interaction between TIPE2 and Smad2 was identified via co‐immunoprecipitation. The results revealed that TIPE2 protein was significantly down‐regulated in epithelial ovarian cancer tissues and correlated with the pathological type of tumor, patients' age, tumor differentiation degree and FIGO stage. TIPE2 and TGF‐β1 appeared to play an opposite role to each other during the progression of human ovarian cancer cells. Furthermore, TIPE2 inhibited the metastasis and EMT of ovarian cancer cells by combining with Smad2 in vitro or in an intraperitoneal metastasis model. Consequently, these findings suggest that TIPE2 plays a crucial inhibitory role in ovarian cancer metastasis by modulating the TGF‐β1/Smad2/EMT signaling pathway and may serve as a potential target for ovarian cancer, providing important direction for future diagnostic and therapeutic strategies. [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]

Anesthetic exposure causes learning and memory impairment, the mechanisms of which remain unknown. It has been reported that tumor necrosis factor-α-inducer protein 8-like 2 (TIPE2) is a newly discovered immune negative regulator that is essential for maintaining immune homeostasis. This study aimed to examine the role of TIPE2 in isoflurane-induced postoperative cognitive decline (POCD).

Drug resistance is a great obstacle to the clinical application of paclitaxel (PTX) in breast cancer treatment. Chemoresistance can be either primary or acquired. Multifarious factors are related to drug resistance. Among these factors, drug-induced autophagy has been shown to contribute to acquired chemoresistance in cancer cells. Additionally, cancer stem cells (CSCs) drive primary chemoresistance. Recent advances regarding TIPE2 demonstrate that TIPE2 enhances osteosarcoma and non-small cell lung cancer cell sensitivity to cisplatin. However, the role of TIPE2 in PTX resistance in breast cancer cells has not been elucidated. Here, the in vitro and in vivo study demonstrated that TIPE2 sensitized breast cancer cells to PTX by suppressing drug-induced autophagy and CSC properties. Mechanistically, we found that TIPE2 activated the AKT/mTOR signalling pathway and inhibited the TAK1/MAPK signalling pathway to suppress drug-induced autophagy. Moreover, TIPE2 inhibited TAK1/NF-κB activation to reduce breast CSC properties. Collectively, our results first elucidated the inhibitory role of TIPE2 in breast cancer chemoresistance. Thus, TIPE2 may be a new target for breast cancer chemotherapy. [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]

Background: The aim of this study was to decide the role of the polarization of macrophages regulated by tumor necrosis factor-α (TNF-α)-induced protein 8-like 2 (TIPE2) in meibomian gland dysfunction (MGD). Methods: Firstly, the secretory function of the meibomian gland (MG) in apolipoprotein E knockout (ApoE-/-) MGD mice and normal mice was detected by oil red staining. Then, the expression levels of markers of M1 and M2 macrophages were detected by immunofluorescence staining in MGD, normal mice, and mild and severe MGD corpses to decide the role of M1 and M2 macrophages in MGD inflammation. Meanwhile, the expression levels of TIPE2 in MGD mice and MGD patients were detected by immunofluorescence staining, and the correlations among TIPE2, M1 and M2 macrophages were analyzed by immunofluorescence double staining in MGD mice and MGD patients. Furthermore, lipopolysaccharide (LPS) and interleulkin-4 (IL-4) were used to induce M1 and M2 polarization of macrophages, and the mRNA level of TIPE2 was detected in M1 and M2 macrophages. Results: Oil red staining showed that eyelid fat congestion was more severe in (ApoE-/-) MGD mice than in normal mice, and the M1 macrophage was the primary inflammatory cell infiltrated in (ApoE-/-) MGD mice (p < 0.05). The results of the immunofluorescence staining showed that the infiltration of macrophages in MGD mice was more obvious than that in the normal group, and M1 macrophage was the dominant group (p < 0.05). Similar to the results of the MGD mouse model, more macrophage infiltration was observed in MGD patients' MG tissues, and there were more M1 cells in the severe group than in the mild group (p < 0.05). Moreover, the expression of TIPE2 was positively correlated with the expression of M2 macrophages in MGD patients and mice MG tissues (p < 0.05). The expression of TIPE2 mRNA in LPS-induced M1 macrophages declined, while the expression of TIPE2 mRNA in IL-4-induced M2 macrophages increased (p < 0.05). Conclusion: M1 macrophage was the dominant group infiltrated in the MG tissue of MGD, and TIPE2 is a potential anti-inflammatory target for preventing the development of MGD by promoting the M2 polarization of macrophages. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic relapsing and progressive inflammatory disease of the colon. TIPE2 is a negative regulator of innate and adaptive immunity that maintains immune homeostasis. We found that TIPE2 was highly expressed in mucosa of mice with colitis. However, the role of TIPE2 in colitis remains unclear. We induced colitis in mice with dextran sulfate sodium (DSS) and treated them with TIPE2, and investigated the inflammatory activity of the colon in vivo by cytokines detection and histopathological analyses. We also measured inflammatory alteration and tight junctions induced by DSS in vitro. The results demonstrated that administration of TIPE2 promoted the severity of colitis in mice and human colon epithelial cells. Furthermore, TIPE2 aggravated intestinal epithelial barrier dysfunction by decreasing the expression of the tight junction proteins Occludin, Claudin-1 and ZO-1. In addition, TIPE2 exacerbated intestinal inflammatory response by inhibiting the expression of SOCS3, remarkably activating JAK2/STAT3 signaling pathway, and increasing the translocation of phosphorylated STAT3 into the nucleus. Silencing of TIPE2 attenuated the DSS-induced activation of JAK2/STAT3, thereby rescuing epithelial inflammatory injury and restoring barrier dysfunction. These results indicate that TIPE2 augments experimental colitis and disrupted the integrity of the intestinal epithelial barrier by activating the JAK2/STAT3/SOCS3 signaling pathway. • TIPE2 is highly expressed in mucosa of mice with colitis. • TIPE2 administration promotes the severity of experimental colitis. • TIPE2 aggravates intestinal epithelial barrier dysfunction by decreasing the expression of the tight junction proteins. • TIPE2 may act as a pro-inflammatory factor by activating the JAK2/STAT3 pathway through inhibiting SOCS3 expression. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2) is encoded by TNFAIP8L2 and is a newly identified negative regulator of natural and acquired immunity that plays a critical function in maintaining immune homeostasis. Recently, CAR-NK immune cell therapy has been a focus of major research efforts as a novel cancer therapeutic strategy. TIPE2 is a potential checkpoint molecule for immune cell maturation and antitumor immunity that could be used as a novel NK cell-based immunotherapeutic approach. In this study, we explored the expression of TNFAIP8L2 across various tumor types and found that TNFAIP8L2 was highly expressed in most tumor types and correlated with prognosis. Survival analysis showed that TNFAIP8L2 expression was predictive of improved survival in cervical-squamous-cell-carcinoma (CESC), sarcoma (SARC) and skin-cutaneous-melanoma (SKCM). Conversely, TNFAIP8L2 expression predicted poorer survival in acute myeloid leukemia (LAML), lower-grade-glioma (LGG), kidney-renal-clear-cell-carcinoma (KIRC) and uveal-melanoma (UVM). Analysis of stemness features and immune cell infiltration indicated that TNFAIP8L2 was significantly associated with cancer stem cell index and increased macrophage and dendritic cell infiltration. Our data suggest that TNFAIP8L2 may be a novel immune checkpoint biomarker across different tumor types, particularly in LAML, LGG, KIRC and UVM, and may have further utility as a potential target for immunotherapy.

Intracerebral hemorrhage (ICH) is a serious disease with high mortality and morbidity, and effective treatment is limited. A large amount of evidence suggests that the inflammatory response contributes to secondary brain damage following ICH. TIPE2 is an essential negative regulator of both innate and adaptive immunity, and depletion of TIPE2 causes inflammatory disease. However, the possible role of TIPE2 following ICH has not been reported. In this study, we investigated TIPE2 levels and inflammation in microglia treated with erythrocyte lysate in vitro. In addition, we analyzed the role of Bcl-2/Bax/cleaved caspase-3 apoptotic pathways in ICH mice. Furthermore, we observed proinflammatory cytokine production, BBB disruption, cerebral water content and neurological damage in ICH mice. We found that TIPE2 levels were significantly decreased in erythrocyte lysate-treated microglia compared to control microglia.Upregulation of TIPE2 decreased microglia activation and cytokine production and accelerated brain damage in ICH mice. Furthermore, upregulation of TIPE2 decreased the higher ratio of Blc-2/Bax and increased cleaved caspase-3 levels in ICH mice. In addition, upregulation of TIPE2 attenuated proinflammatory cytokine production, BBB disruption, and severe brain inflammation after ICH. These results demonstrated that TIPE2 was negatively correlated with the pathogenesis of ICH, which prevented brain injury and attenuated deleterious inflammatory responses following ICH. TIPE2 might serve as a novel target for ICH therapy. • TIPE2 levels were significantly decreased in erythrocyte lysate-treated macrophages compared to control macrophages. • Upregulation of TIPE2decreased macrophage activation and cytokine production and accelerated braindamage in ICH mice. • Upregulation of TIPE2attenuated proinflammatory cytokine production, BBB disruption, and severe brain inflammation after ICH. • TIPE2 was negativelycorrelated with the pathogenesis of ICH, and might serve as a novel target forICH therapy. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) possesses potent anti-inflammatory effect. However, if TIPE2 ameliorates sciatic nerve injury (SNI)-induced inflammation and pain remains undiscussed, and the underlying role TAK1 in it were unknown. To verify our imagine, we performed SNI surgery, and analyzed expression and colocalization of TIPE2 and TAK1 in spinal cord and dorsal root neurons (DRG) by immunofluorescence staining and western blot. And the biological analysis, inflammatory factors, and pathological improvement were determined, and the regulation of TIPE2 in TAK1, phosphor-NF-κB, phospho-JNK was also tested by immunofluorescence staining and western blot. Experimental results showed the parabola-like change of TIPE2 and rising expression of TAK1 in spinal cord and DRG. And intrathecal TIPE2 injection could significantly improve the status of SNI rats, inhibit level of IL-6, IL-10 and TNF-α, raise the thermal withdrawal relax latency and mechanical withdrawal thresholds. Meanwhile, we also detected how TIPE2 regulated TAK1, and the downstream pathway NF-κB and JNK. The result indicated that TIPE2 could reduce TAK1 expression, and make NF-κB and JNK inactivated. To deeply discuss the potential mechanism, we injected TAK1 oligodeoxynucleotide into rats, and found that TIPE2 exerted the protective role against SNI through TAK1. In brief, TIPE2 reduced expression of TAK1, thereby inhibiting activation of NF-kB and JNK, further improving the neuroinflammation and neuropathic pain. TIPE2 played a protective role in sciatic nerve injury rats through regulating TAK1. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) as a novel negative immune regulator plays an important role in several human diseases. However, its influences in cervical cancer and preeclampsia (PE) remain unclear. This study aims to explore the important role of TIPE2 in cervical cancer and PE via regulating cell invasion. TIPE2 expression in the cervical cancer tissues or the placenta of PE patients was detected. Human cervical cancer cell lines and trophoblasts were transfected with adenovirus expressing human TIPE2 and green fluorescent protein (GFP) (Ad-TIPE2), or the control adenovirus expressing GFP (Ad-GFP). Xenograft models were also constructed on nude mice, aiming to clarify how TIPE2 affects in vivo growth of cervical cancer cells. TIPE2 was down-regulated in the tumor tissues or placenta of patients with cervical cancer or PE. As a result, CaSKi and Hela cells in the Ad-TIPE2 group had decreased migration and invasion, with significant up-regulations of TIPE2 and E-cadherin, but down-regulations of β -catenin and N-cadherin. Ad-TIPE2 decreased the volume and weight of xenograft tumors in the nude mice, with the down-regulation of Ki67. The quantity of cells (HTR8/SVneo and JEG3 cells) transfected with Ad-TIPE2 had increased, with up-regulations of TIPE2, matrix metalloproteinase (MMP)-2 and MMP-9. TIPE2 overexpression could reduce the invasion and migration of cervical cancer cells via inhibiting the epithelial-mesenchymal transition (EMT) process, and promote trophocyte invasion via upregulating the expression of MMPs, and it may be used as a potential therapeutic target for cervical cancer and PE. [ABSTRACT FROM AUTHOR]

Abstract Background Childhood asthma is a common respiratory disease characterized by airway inflammation. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) has been found to be involved in the progression of asthma. This study aimed to explore the role of TIPE2 in the regulation of airway smooth muscle cells (ASMCs), which are one of the main effector cells in the development of asthma. Materials and methods ASMCs were transfected with pcDNA3.0-TIPE2 or si-TIPE2 for 48 h and then treated with platelet-derived growth factor (PDGF)-BB. Cell proliferation of ASMCs was measured using the MTT assay. Cell migration of ASMCs was determined by a transwell assay. The mRNA expression levels of calponin and smooth muscle protein 22α (SM22α) were measured using qRT-PCR. The levels of TIPE2, calponin, SM22α, PI3K, p-PI3K, Akt, and p-Akt were detected by Western blotting. Results Our results showed that PDGF-BB treatment significantly reduced TIPE2 expression at both the mRNA and protein levels in ASMCs. Overexpression of TIPE2 inhibited PDGF-BB-induced ASMC proliferation and migration. In addition, overexpression of TIPE2 increased the expression of calponin and SM22α in PDGF-BB-stimulated ASMCs. However, an opposite effect was observed with TIPE2 knockdown. Furthermore, TIPE2 overexpression blocked PDGF-BB-induced phosphorylation of PI3K and Akt, whereas the expression of p-PI3K and p-Akt were aggravated by TIPE2 knockdown. Additionally, the effects of TIPE2 overexpression and TIPE2 knockdown were altered by IGF-1 and LY294002 treatments, respectively. Conclusions Our findings demonstrate that TIPE2 inhibits PDGF-BB-induced ASMC proliferation, migration, and phenotype switching via the PI3K/Akt signaling pathway. Thus, TIPE2 may be a potential therapeutic target for the treatment of asthma.

Purpose: Although recent studies have highlighted the link of TIPE2 and asthma airway inflammation, its roles and molecular mechanisms in different asthma inflammatory phenotypes remain largely unknown. We evaluated sputum TIPE2 expression level and its correlation with different asthma phenotypes. Additionally, we explored the roles and mechanism of TIPE2 in M1 polarization of macrophages. Methods: A total of 102 asthma patients who underwent sputum induction were enrolled to evaluate the expression level of TIPE2 and its association with different asthma phenotypes. To explore the roles and mechanism of TIPE2 in M1 polarization of macrophages, THP-1 monocytes stimulated with phorbol-12-myristate-13-acetate, were used as a model of undifferentiated (M0) macrophages, and M0 macrophages were treated with lipopolysaccharide to induce M1 macrophages. Results: The sputum TIPE2 level was significantly lower in patients with neutrophilic asthma (NA) and higher in patients with eosinophilic asthma (EA) compared with patients with paucigranulocytic asthma. The levels of IL-1β, TNF-α and IL-6 were highest in NA compared with other groups. TIPE2 levels in sputum negatively correlated with IL-1β and TNF-α levels but positively correlated with IL-4, IL-5, IL-13, and IL-10 levels (P < 0.05). In vitro , TIPE2 enhanced Nrf2/HO-1 pathway activation in macrophages and inhibited LPS-induced M1 macrophage differentiation and related cytokine release. Further analysis showed that the Nrf2 inhibitor ML385 weakened TIPE2-induced activation of the Nrf2/HO-1 pathway, as well as TIPE2-induced suppression in M1 polarization of macrophage and inflammatory cytokines secretion. Conclusions: TIPE2 expression level was highly down-regulated in NA and was negatively correlated with inflammatory factors (IL-1β and TNF-α). Aberrant expression of TIPE2 may target the Nrf2/HO-1 pathway to inhibit M1 macrophage–related neutrophilic inflammation in asthma. [ABSTRACT FROM AUTHOR]

PurposeAlthough recent studies have highlighted the link of TIPE2 and asthma airway inflammation, its roles and molecular mechanisms in different asthma inflammatory phenotypes remain largely unknown. We evaluated sputum TIPE2 expression level and its correlation with different asthma phenotypes. Additionally, we explored the roles and mechanism of TIPE2 in M1 polarization of macrophages.MethodsA total of 102 asthma patients who underwent sputum induction were enrolled to evaluate the expression level of TIPE2 and its association with different asthma phenotypes. To explore the roles and mechanism of TIPE2 in M1 polarization of macrophages, THP-1 monocytes stimulated with phorbol-12-myristate-13-acetate, were used as a model of undifferentiated (M0) macrophages, and M0 macrophages were treated with lipopolysaccharide to induce M1 macrophages.ResultsThe sputum TIPE2 level was significantly lower in patients with neutrophilic asthma (NA) and higher in patients with eosinophilic asthma (EA) compared with patients with paucigranulocytic asthma. The levels of IL-1β, TNF-α and IL-6 were highest in NA compared with other groups. TIPE2 levels in sputum negatively correlated with IL-1β and TNF-α levels but positively correlated with IL-4, IL-5, IL-13, and IL-10 levels (P < 0.05). In vitro, TIPE2 enhanced Nrf2/HO-1 pathway activation in macrophages and inhibited LPS-induced M1 macrophage differentiation and related cytokine release. Further analysis showed that the Nrf2 inhibitor ML385 weakened TIPE2-induced activation of the Nrf2/HO-1 pathway, as well as TIPE2-induced suppression in M1 polarization of macrophage and inflammatory cytokines secretion.ConclusionsTIPE2 expression level was highly down-regulated in NA and was negatively correlated with inflammatory factors (IL-1β and TNF-α). Aberrant expression of TIPE2 may target the Nrf2/HO-1 pathway to inhibit M1 macrophage–related neutrophilic inflammation in asthma.

Zhengzhong Gu,1 Xiaohan Cui,2 Pengda Sun,1 Xudong Wang1 1Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 2Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of ChinaCorrespondence: Xudong WangDepartment of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun 130041 Jilin Province, People’s Republic of ChinaTel +86 13514406378Email wangxudong1971@126.comAbstract: 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.Keywords: TIPE2, inflammation, immune homeostasis, tumor, tumorigenesis, metastasis

Osteoarthritis (OA) pain is often associated with the expression of tumor necrosis factor alpha (TNF-α), suggesting that TNF-α is one of the main contributing factors that cause inflammation, pain, and OA pathology. Thus, inhibition of TNF-α could potentially improve OA symptoms and slow disease progression. Anti-TNF-α treatments with antibodies, however, require multiple treatments and cannot entirely block TNF-α. TNF-α-induced protein 8-like 2 (TIPE2) was found to regulate the immune system's homeostasis and inflammation through different mechanisms from anti-TNF-α therapies. With a single treatment of adeno-associated virus (AAV)-TIPE2 gene delivery in the accelerated aging Zmpste24 -/- (Z24 -/- ) mouse model, we found differences in Safranin O staining intensity within the articular cartilage (AC) region of the knee between TIPE2-treated mice and control mice. The glycosaminoglycan content (orange-red) was degraded in the Z24 -/- cartilage while shown to be restored in the TIPE2-treated Z24 -/- cartilage. We also observed that chondrocytes in Z24 -/- mice exhibited a variety of senescent-associated phenotypes. Treatment with TIPE2 decreased TNF-α-positive cells, β-galactosidase (β-gal) activity, and p16 expression seen in Z24 -/- mice. Our study demonstrated that AAV-TIPE2 gene delivery effectively blocked TNF-α-induced inflammation and senescence, resulting in the prevention or delay of knee OA in our accelerated aging Z24 -/- mouse model., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

The TIPE2 (tumor necrosis factor-alpha-induced protein 8-like 2) protein is a major regulator of cancer and inflammatory diseases. The availability of its sequence and structure, as well as the critical amino acids involved in its ligand binding, provides insights into its function and helps greatly identify novel drug candidates against TIPE2 protein. With the current advances in deep learning and molecular dynamics simulation-based drug screening, large-scale exploration of inhibitory candidates for TIPE2 becomes possible. In this work, we apply deep learning-based methods to perform a preliminary screening against TIPE2 over several commercially available compound datasets. Then, we carried a fine screening by molecular dynamics simulations, followed by metadynamics simulations. Finally, four compounds were selected for experimental validation from 64 candidates obtained from the screening. With surprising accuracy, three compounds out of four can bind to TIPE2. Among them, UM-164 exhibited the strongest binding affinity of 4.97 µM and was able to interfere with the binding of TIPE2 and PIP2 according to competitive bio-layer interferometry (BLI), which indicates that UM-164 is a potential inhibitor against TIPE2 function. The work demonstrates the feasibility of incorporating deep learning and MD simulation in virtual drug screening and provides high potential inhibitors against TIPE2 for drug development. [ABSTRACT FROM AUTHOR]

The TIPE2 (tumor necrosis factor-alpha-induced protein 8-like 2) protein is a major regulator of cancer and inflammatory diseases. The availability of its sequence and structure, as well as the critical amino acids involved in its ligand binding, provides insights into its function and helps greatly identify novel drug candidates against TIPE2 protein. With the current advances in deep learning and molecular dynamics simulation-based drug screening, large-scale exploration of inhibitory candidates for TIPE2 becomes possible. In this work, we apply deep learning-based methods to perform a preliminary screening against TIPE2 over several commercially available compound datasets. Then, we carried a fine screening by molecular dynamics simulations, followed by metadynamics simulations. Finally, four compounds were selected for experimental validation from 64 candidates obtained from the screening. With surprising accuracy, three compounds out of four can bind to TIPE2. Among them, UM-164 exhibited the strongest binding affinity of 4.97 µM and was able to interfere with the binding of TIPE2 and PIP2 according to competitive bio-layer interferometry (BLI), which indicates that UM-164 is a potential inhibitor against TIPE2 function. The work demonstrates the feasibility of incorporating deep learning and MD simulation in virtual drug screening and provides high potential inhibitors against TIPE2 for drug development.

Tumor necrosis factor-α inducible protein-8 (TIPE2), initially recognized as a negative immune regulator, exerts an important role in suppressing the progression of numerous cancers. In our previous investigation, we found that TIPE2 expression displayed a decrease or absence in gastric tumor tissue, and the overexpression of TIPE2 suppressed the growth of gastric cancer tumors and cells, demonstrating that TIPE2 could be a potential medicinal target for gastric cancer treatment. However, it’s seldomly reported that several medicinal agents or candidates targeted TIPE2 for treating diseases, including gastric cancer. To identify the candidate targeting TIPE2 to fight against gastric cancer, several extractions from traditional natural medicinal plants with anti-tumor functions were employed to screen the active compounds according to bioassay-guided isolation. Interestingly, gracillin, a component from the ethyl acetate extraction of Rhizoma Paridis, was identified to induce the expression of TIPE2 and inhibit the cell proliferation in gastric cancer BGC-823 cells. Furthermore, the underlying mechanisms that restrain gastric cancer were evaluated by clone formation, EdU staining, flow cytometry, and other assays. Meanwhile, the role of TIPE2 in the anti-tumor effect of gracillin was elucidated via the use of siTIPE2 RNA. It was determined that gracillin could fight against gastric cancer cells by inhibiting the cell proliferation participated by the PI3K/AKT pathway and cell cycle arrest, suppressing the EMT pathway-regulating cell migration, and inducing bcl2-associated mitochondrial apoptosis. Additionally, TIPE2 maybe contribute to the benefits of gracillin. These results of the present study are an important step toward the medicinal development of gracillin, and are also of use in understanding the effect of TIPE2 as a potential tumor target.

Tumor necrosis factor-α inducible protein-8 (TIPE2), initially recognized as a negative immune regulator, exerts an important role in suppressing the progression of numerous cancers. In our previous investigation, we found that TIPE2 expression displayed a decrease or absence in gastric tumor tissue, and the overexpression of TIPE2 suppressed the growth of gastric cancer tumors and cells, demonstrating that TIPE2 could be a potential medicinal target for gastric cancer treatment. However, it's seldomly reported that several medicinal agents or candidates targeted TIPE2 for treating diseases, including gastric cancer. To identify the candidate targeting TIPE2 to fight against gastric cancer, several extractions from traditional natural medicinal plants with anti-tumor functions were employed to screen the active compounds according to bioassay-guided isolation. Interestingly, gracillin, a component from the ethyl acetate extraction of Rhizoma Paridis , was identified to induce the expression of TIPE2 and inhibit the cell proliferation in gastric cancer BGC-823 cells. Furthermore, the underlying mechanisms that restrain gastric cancer were evaluated by clone formation, EdU staining, flow cytometry, and other assays. Meanwhile, the role of TIPE2 in the anti-tumor effect of gracillin was elucidated via the use of siTIPE2 RNA. It was determined that gracillin could fight against gastric cancer cells by inhibiting the cell proliferation participated by the PI3K/AKT pathway and cell cycle arrest, suppressing the EMT pathway-regulating cell migration, and inducing bcl2-associated mitochondrial apoptosis. Additionally, TIPE2 maybe contribute to the benefits of gracillin. These results of the present study are an important step toward the medicinal development of gracillin, and are also of use in understanding the effect of TIPE2 as a potential tumor target. [ABSTRACT FROM AUTHOR]

Background: Childhood asthma is a common respiratory disease characterized by airway inflammation. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) has been found to be involved in the progression of asthma. This study aimed to explore the role of TIPE2 in the regulation of airway smooth muscle cells (ASMCs), which are one of the main effector cells in the development of asthma.Materials and Methods: ASMCs were transfected with pcDNA3.0-TIPE2 or si-TIPE2 for 48 h and then treated with platelet-derived growth factor (PDGF)-BB. Cell proliferation of ASMCs was measured using the MTT assay. Cell migration of ASMCs was determined by a transwell assay. The mRNA expression levels of calponin and smooth muscle protein 22α (SM22α) were measured using qRT-PCR. The levels of TIPE2, calponin, SM22α, PI3K, p-PI3K, Akt, and p-Akt were detected by Western blotting.Results: Our results showed that PDGF-BB treatment significantly reduced TIPE2 expression at both the mRNA and protein levels in ASMCs. Overexpression of TIPE2 inhibited PDGF-BB-induced ASMC proliferation and migration. In addition, overexpression of TIPE2 increased the expression of calponin and SM22α in PDGF-BB-stimulated ASMCs. However, an opposite effect was observed with TIPE2 knockdown. Furthermore, TIPE2 overexpression blocked PDGF-BB-induced phosphorylation of PI3K and Akt, whereas the expression of p-PI3K and p-Akt were aggravated by TIPE2 knockdown. Additionally, the effects of TIPE2 overexpression and TIPE2 knockdown were altered by IGF-1 and LY294002 treatments, respectively.Conclusions: Our findings demonstrate that TIPE2 inhibits PDGF-BB-induced ASMC proliferation, migration, and phenotype switching via the PI3K/Akt signaling pathway. Thus, TIPE2 may be a potential therapeutic target for the treatment of asthma. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is one of the major reasons of cancer-associated deaths due to poor diagnosis, high metastasis and drug resistance. Therefore, it is important to understand the cellular and molecular mechanisms of pancreatic cancer to identify new targets for the treatment. TIPE2 is an essential regulator of tumor apoptosis, inflammation and immune homeostasis. However, the role of TIPE2 is still not fully understood in pancreatic cancer. In this study, we found the expression of TIPE2 was decreased in pancreatic cancer tissues compare to paracancerous tissues, which was negatively correlated with tumor size in patients. Overexpression of TIPE2 significantly decreased cell proliferation, metastasis and increased apoptotic events in pancreatic cancer cell lines. Moreover, the results obtained from real time PCR and western blot revealed that TIPE2 was also involved in inhibiting MMPs and N-Cadherin expression while increasing Bax expression in pancreatic cancer cells. Similarly, TIPE2 could inhibit tumor growth in vivo, decrease the expression of Ki-67 and N-Cadherin, and increase the expression of Bax by IHC analysis in tumor tissues isolated from tumor-bearing mice. Mechanistic studies exhibited that TIPE2 might suppress pancreatic cancer development through inhibiting PI3K/AKT and Raf/MEK/ERK signaling pathways triggered by TGFβ1. Moreover, the tumor-infiltrating lymphocytes from tumor-bearing mice were analyzed by flow cytometry, and showed that TIPE2 could promote T cell activation to exert an anti-tumor effect possibly through activation of DCs in a TGFβ1 dependent manner. In general, we described the multiple regulatory mechanisms of TIPE2 in pancreatic tumorigenesis and tumor microenvironment, which suggested TIPE2 may act as a potential therapeutic target in pancreatic cancer.

Pancreatic cancer is one of the major reasons of cancer-associated deaths due to poor diagnosis, high metastasis and drug resistance. Therefore, it is important to understand the cellular and molecular mechanisms of pancreatic cancer to identify new targets for the treatment. TIPE2 is an essential regulator of tumor apoptosis, inflammation and immune homeostasis. However, the role of TIPE2 is still not fully understood in pancreatic cancer. In this study, we found the expression of TIPE2 was decreased in pancreatic cancer tissues compare to paracancerous tissues, which was negatively correlated with tumor size in patients. Overexpression of TIPE2 significantly decreased cell proliferation, metastasis and increased apoptotic events in pancreatic cancer cell lines. Moreover, the results obtained from real time PCR and western blot revealed that TIPE2 was also involved in inhibiting MMPs and N-Cadherin expression while increasing Bax expression in pancreatic cancer cells. Similarly, TIPE2 could inhibit tumor growth in vivo , decrease the expression of Ki-67 and N-Cadherin, and increase the expression of Bax by IHC analysis in tumor tissues isolated from tumor-bearing mice. Mechanistic studies exhibited that TIPE2 might suppress pancreatic cancer development through inhibiting PI3K/AKT and Raf/MEK/ERK signaling pathways triggered by TGFβ1. Moreover, the tumor-infiltrating lymphocytes from tumor-bearing mice were analyzed by flow cytometry, and showed that TIPE2 could promote T cell activation to exert an anti-tumor effect possibly through activation of DCs in a TGFβ1 dependent manner. In general, we described the multiple regulatory mechanisms of TIPE2 in pancreatic tumorigenesis and tumor microenvironment, which suggested TIPE2 may act as a potential therapeutic target in pancreatic cancer. [ABSTRACT FROM AUTHOR]

A systematic and flexible immunoregulatory network is required to ensure the proper outcome of antiviral immune signaling and maintain homeostasis during viral infection. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2), a novel immunoregulatory protein, has been extensively studied in inflammatory response, apoptosis, and cancer. However, the function of TIPE2 in antiviral innate immunity is poorly clarified. In this study, we reported that the expression of TIPE2 declined at the early period and then climbed up in macrophages under RNA virus stimulation. Knockout of TIPE2 in the macrophages enhanced the antiviral capacity and facilitated type I interferon (IFN) signaling after RNA viral infection both in vitro and in vivo. Consistently, overexpression of TIPE2 inhibited the production of type I IFNs and pro-inflammatory cytokines, and thus promoted the viral infection. Moreover, TIPE2 restrained the activation of TBK1 and IRF3 in the retinoic acid inducible gene-I (RIG-I)-like receptors (RLR) signaling pathway by directly interacting with retinoic acid inducible gene-I (RIG-I). Taken together, our results suggested that TIPE2 suppresses the type I IFN response induced by RNA virus by targeting RIG-I and blocking the activation of downstream signaling. These findings will provide new insights to reveal the immunological function of TIPE2 and may help to develop new strategies for the clinical treatment of RNA viral infections.

A systematic and flexible immunoregulatory network is required to ensure the proper outcome of antiviral immune signaling and maintain homeostasis during viral infection. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2), a novel immunoregulatory protein, has been extensively studied in inflammatory response, apoptosis, and cancer. However, the function of TIPE2 in antiviral innate immunity is poorly clarified. In this study, we reported that the expression of TIPE2 declined at the early period and then climbed up in macrophages under RNA virus stimulation. Knockout of TIPE2 in the macrophages enhanced the antiviral capacity and facilitated type I interferon (IFN) signaling after RNA viral infection both in vitro and in vivo. Consistently, overexpression of TIPE2 inhibited the production of type I IFNs and pro-inflammatory cytokines, and thus promoted the viral infection. Moreover, TIPE2 restrained the activation of TBK1 and IRF3 in the retinoic acid inducible gene-I (RIG-I)-like receptors (RLR) signaling pathway by directly interacting with retinoic acid inducible gene-I (RIG-I). Taken together, our results suggested that TIPE2 suppresses the type I IFN response induced by RNA virus by targeting RIG-I and blocking the activation of downstream signaling. These findings will provide new insights to reveal the immunological function of TIPE2 and may help to develop new strategies for the clinical treatment of RNA viral infections. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Rheumatoid arthritis (RA) is a prevalent chronic autoimmune disease posing a considerable burden on both individuals and society. Tumor necrosis induced protein 8-like 2 (TIPE2), closely related to PEST-containing nuclear protein (PCNP) expression, is an immune-related protein potentially involved in the pathogenesis of autoimmune diseases. In this study, we aimed to assess differential expressions of TIPE2 and PCNP in peripheral blood mononuclear cells (PBMCs) between active and inactive RA patients. MATERIALS AND METHODS: Relevant studies were selected from Medline, Google Scholar, Web of Science, and China National Knowledge Infrastructure (CNKI). Only observational studies (irrespective of publication status, language, or blinding), which compared patients in high disease activity, irrespective of the sample size, with patients in low disease activity of RA were evaluated. RESULTS: Four studies were included with 248 patients, 138 in the active group and 110 in the inactive group. Three studies provided data on TIPE2 expression levels, where 106 patients were divided into the active group and 88 patients were divided into the inactive group. The pooled analysis revealed a statistically significant difference between the two groups (WMD: 5.60; 95% CI: 5.02-6.18). Two studies provided data on PCNP expression levels, where 64 patients were divided into the active group and 44 patients were divided into the inactive group. The pooled analysis revealed a statistically significant difference between the two groups (WMD: 7.76; 95% CI: 3.09-12.43). CONCLUSIONS: The expression levels of TIPE2 and PCNP are significantly increased in PBMCs of active RA patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To detect the expressions of tumor necrosis factor-α-induced protein-8-like 2 (TIPE2) and tissue factor (TF) in peripheral blood mononuclear cells (PBMCs) of patients with acute exacerbation of bronchial asthma (BA), and to analyze their associations with changes in inflammatory factors and T lymphocytes. PATIENTS AND METHODS: A total of 59 patients with BA treated in our hospital from February 2018 to April 2019 were selected as objects, including 30 cases in the acute exacerbation phase (BA group) and 29 in the remission phase (RE group). During the same period, 28 people receiving physical examinations were selected as healthy controls (Control group). The proportion of eosinophils in the sputum and the fractional exhaled nitric oxide (FeNO) level were detected in each subject. Blood samples were collected in patients of BA group and Control group, aiming to isolate PBMCs. Then, the messenger RNA (mRNA) expressions of TIPE2 and TF in PBMCs were determined via reverse transcription-polymerase chain reaction (RT-PCR). Serum levels of interleukin-1β (IL-1β) and IL-6 in BA group and Control group were determined via enzyme-linked immunosorbent assay (ELISA), and protein expressions of serum T helper 1 (Th1) and Th2 cells in BA group and Control group were detected using Western blotting. RESULTS: Compared with those in Control group, the proportion of eosinophils and Fe-NO level increased in BA and RE group, which were more pronounced in BA group. Downregulated mRNA level of TIPE2, and upregulated TF were detected in BA and RE groups compared to those of Control group, and the expression changes were more significant in the former group. Enzyme-linked immunosorbent assay (ELISA) data showed that serum levels of IL-1β and IL-6 were significantly elevated in BA and RE groups in comparison to Control group, especially BA group. In addition, protein level of Th1 cells was downregulated, while that of Th2 was upregulated in BA group and RE group compared to those of Control group, and a more significant change was observed in BA group compared to that of RE group. CONCLUSIONS: In patients with acute exacerbation of BA, the expression of TIPE2 in PBMCs declined, while that of TF rose, which were negatively correlated with each other. Moreover, the proportion of Th1 cells declined in patients with acute exacerbation of BA, indicating that it is associated with the lung function, inflammatory level and proportion of eosinophils. [ABSTRACT FROM AUTHOR]

Abstract Evaluating the risk category of gastrointestinal stromal tumors (GISTs) is crucial for predicting prognosis and choosing treatment strategies, and tumor metastasis usually represent poor prognosis. Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) is a novel described tumor suppressor. In the present study, TIPE2 expression was detected using a total of 96 human GIST specimens by immunohistochemistry. The effect of TIPE2 on proliferation and invasiveness of GIST cells and its related mechanisms were explored in vitro. It was found that TIPE2 expression was gradually decreased in accordance with GIST risk grades and negatively associated with tumor size, mitotic count and risk category. Moreover, TIPE2 was identified as a biomarker for evaluating the risk grade of GIST. TIPE2 markedly suppressed the viability, colony formation, migration and invasion of GIST cells. Furthermore, TIPE2 induced apoptosis and suppressed MMP-9 expression of GIST cells by targeting Rac1. In conclusion, these results indicate that TIPE2 plays a pivotal role in the progression of GIST. TIPE2 serves as a promising biomarker for evaluating GIST risk grade and a potential target for treatment of GIST.

Abstract 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 Background Gastric cancer (GC) is one of the most common malignant diseases with high morbidity and mortality, especially in Asian countries. During the GC developing progress, TIPE2, a member of TNF-alpha induced protein 8-like (TNFAIP8L) family, may play important roles. However, the molecular mechanisms of TIPE2 contributing to cell proliferation and tumor growth are poorly understood in GC. We performed flow cytometry to detect the cell cycle of TIPE2-knockdown GC cells under lipopolysaccharide (LPS) stimulation. Methods We measured TIPE2 expression in tumor samples from 46 human GC patients at mRNA level by Realtime PCR and in 68 pairs of GC tissues at protein level by immunohistochemistry. We established stable TIPE2 knockdown SGC7901 and BGC823 cell lines and performed CCK-8 and EdU proliferation assays under the stimulation of LPS. And then we analyzed AKT, IκBα and ERK phosphorylation levels, as well as cycle related proteins CDK4 and CyclinD3 in the stable TIPE2 knockdown SGC7901 and BGC823 cells. Results Our present studies indicated that the expression of TIPE2 was significantly decreased in tumor tissues compared to distant mucosa tissues in human GC patients. TIPE2 inhibited proliferation stimulated by LPS in SGC7901 and BGC823 cells. Silencing of TIPE2 significantly decreased cell G0/G1 phase ratio and increased G2/M phase. TIPE2 knockdown SGC7901 and BGC823 cells declined AKT and IκBα phosphorylation. TIPE2’s action on GC cell cycle was. Conclusions Our results demonstrated that TIPE2 is a novel tumor suppressor gene that inhibits GC growth may mediated via AKT and IκBα phosphorylated activation. We revealed that TIPE2 may effectively interdict neoplasm development, which has potential clinical application values for GC targeted therapies.

Abstract 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.

Unlike other members of the tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8/TIPE) family that play a carcinogenic role and regulate apoptosis, TNFAIP8-like 2 (TIPE2) can not only maintain immune homeostasis but also regulate inflammation. TIPE2 mainly restrains the activation of T cell receptor (TCR) and Toll-like receptors (TLR), regulating its downstream signaling pathways, thereby regulating inflammation. Interestingly, TIPE2 is abnormally expressed in many inflammatory diseases and may promote or inhibit inflammation in different diseases. This review summarizes the molecular target and cellular function of TIPE2 in immune cells and inflammatory diseases and the underlying mechanism by which TIPE2 regulates inflammation. The function and mechanism of TIPE2 in asthma is also explained in detail. TIPE2 is abnormally expressed in asthma and participates in the pathogenesis of different phenotypes of asthma through regulating multiple inflammatory cells’ activity and function. Considering the indispensable role of TIPE2 in asthma, TIPE2 may be an effective therapeutic target in asthma. However, the available data are insufficient to provide a full understanding of the complex role of TIPE2 in human asthma. Further study is still necessary to explore the possible mechanism and functions of TIPE2 in different asthma phenotypes. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate whether TIPE2 participates in the protective actions of dexmedetomidine (DEX) in a mouse model of sepsis-induced acute lung injury (ALI). We administered TIPE2 adeno-associated virus (AAV-TIPE2) intratracheally into the lungs of mice. Control mice were infected with an adeno-associated virus expressing no transgene. Three weeks later, an animal model of caecal ligation-perforation (CLP)-induced sepsis was established. DEX was administered intravenously 30 min after CLP. Twenty-four hours after sepsis, lung injury was assayed by lung histology, the ratio of polymorphonuclear leukocytes (PMNs) to total cells in the bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) activity, BALF protein content and the lung wet-to-dry (W/D) weight ratio. Proinflammatory factor levels in the BALF of mice were measured. The protein expression levels in lung tissues were analysed by Western blotting. The results showed that DEX treatment markedly mitigated sepsis-induced lung injury, which was characterized by the deterioration of histopathology, histologic scores, the W/D weight ratio and total protein levels in the BALF. Moreover, DEX markedly attenuated sepsis-induced lung inflammation, as evidenced by the decrease in the number of PMNs in the BALF, lung MPO activity and proinflammatory cytokines in the BALF. In addition, DEX dramatically prevented sepsis-induced pulmonary cell apoptosis in mice, as reflected by decreases in the number of TUNEL-positive cells, the protein expression of cleaved caspase-9 and cleaved caspase 3 and the Bax/Bcl-2 ratio. In addition, evaluation of protein expression showed that DEX blocked sepsis-activated JNK phosphorylation and NF-κB p65 nuclear translocation. Similar results were also observed in the TIPE2 overexpression group. Our study demonstrated that DEX inhibits acute inflammation and apoptosis in a murine model of sepsis-stimulated ALI via the upregulation of TIPE2 and the suppression of the activation of the NF-κB and JNK signalling pathways. [ABSTRACT FROM AUTHOR]

Study Question: 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?Summary Answer: 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).What Is Known Already: 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.Study Design, Size, Duration: 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.Participants/materials, Setting, Methods: 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.Main Results and the Role Of Chance: 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).Large Scale Data: N/A.Limitations, Reasons For Caution: 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.Wider Implications Of the Findings: 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.Study Fundings/competing Interest(s): 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. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) can negatively regulate innate immunity and adaptive immunity and participate in the development and progression of various liver diseases, such as hepatitis, liver cirrhosis, and hepatocellular carcinoma, by affecting a variety of signaling pathways. This article summarizes the current research on the involvement of TIPE2 in the pathogenesis of different liver diseases and points out that TIPE2 may become a new target for the treatment of liver diseases. [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]

Abstract 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-ɑ 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-ɑ, 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-ɑ, 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.

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.

Objective To investigate the mRNA expression of tumor necrosis factor-alpha-induced protein 8-like 2( TIPE2) and forkhead box P3( Foxp3) of CD4+CD25+regulatory T cells( Tregs) in peripheral blood mononuclear cells( PBMCs) and their correlation in patients with primary liver cancer. Methods A total of 55 patients with primary liver cancer who visited the outpatient service or were hospitalized in Third Hospital of Hebei Medical University from January 2014 to December 2016 were enrolled as primary liver cancer group,and 35 healthy volunteers were enrolled as control group. The mRNA expression of TIPE2 and Foxp3 in PBMCs was measured,and their correlation with serum biochemical parameters for the liver,alpha-fetoprotein( AFP),blood leukocytes,and tumor size and number was analyzed. The t-test was used for comparison of continuous data between two groups,and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between two groups,and the Pearson correlation analysis was used to investigate correlation. Results There were significant differences between the two groups in alanine aminotransferase( ALT),aspartate aminotransferase( AST),AST/ALT ratio,total bilirubin,white blood cell count,and AFP( all P < 0. 05). Compared with the control group,the primary liver cancer group had significantly lower mRNA expression of TIPE2( 0. 396 ± 0. 174 vs 1. 045 ± 0. 330,t = 12. 187,P < 0. 01) and significantly higher mRNA expression of Foxp3( 4. 498 ± 1. 672 vs 1. 922 ±1. 297,t = 7. 746,P < 0. 01). The mRNA expression of TIPE2 was negatively correlated with serum levels of ALT and AST,AST/ALT ratio,and AFP level( r =-0. 752,-0. 833,-0. 992,and-0. 848,all P < 0. 05),while the mRNA expression of Foxp3 was positively correlated with serum levels of ALT and AST,AST/ALT ratio,and AFP level( r = 0. 449,0. 536,0. 843,and 0. 640,all P < 0. 05). ThemRNA expression of TIPE2 was negatively correlated with that of Foxp3( r =-0. 821,P < 0. 01). Conclusion Liver cancer patients have downregulated mRNA expression of TIPE2 and upregulated mRNA expression of Foxp3,which is correlated with the degree of hepatocellular injury and AFP level. The TIPE2 gene may be involved in the pathogenesis of liver cancer by negative regulation of Treg-mediated immune response. [ABSTRACT FROM AUTHOR]

Objective: Tumour necrosis factor-α-induced protein 8-like 2 (TIPE2) has strong anti-inflammatory properties. However, it is unknown whether increased TIPE2 is protective against lipopolysaccharide (LPS)-induced ALI. In the current study, we aimed to investigate whether increased TIPE2 can exert protective effects in a mouse model of ALI induced by LPS. Methods: We administered TIPE2 adeno-associated virus (AAV-TIPE2) intratracheally into the lungs of mice. Three weeks later, ALI was induced by intratracheal injection of LPS into BALB/c mice. Twenty-four hours later, lung bronchoalveolar lavage fluid (BALF) was acquired to analyse cells and protein, arterial blood was collected for arterial blood gas analysis and the determination of pro-inflammatory factor levels, and lung issues were collected for histologic examination, transmission electron microscopy (TEM), TUNEL staining, wet/dry (W/D) weight ratio analysis, myeloperoxidase (MPO) activity analysis and blot analysis of protein expression. Results: We found that TIPE2 overexpression markedly mitigated LPS-induced lung injury, which was evaluated by the deterioration of histopathology, histologic scores, the W/D weight ratio, and total protein expression in the BALF. Moreover, TIPE2 overexpression markedly attenuated lung inflammation, as evidenced by the downregulation of polymorphonuclear neutrophils (PMNs) in the BALF, lung MPO activity, and pro-inflammatory cytokine levels in the serum. Moreover, TIPE2 overexpression not only dramatically prevented LPS-induced pulmonary cell apoptosis in mice but also blocked LPS-activated JNK phosphorylation and NF-κB p65 nuclear translocation. Conclusions: Our study shows that the increased expression of AAV-mediated TIPE2 in the lungs of mice inhibits acute inflammation and apoptosis and suppresses the activation of NF-κB and JNK in a murine model of ALI. [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]

Neuroinflammation plays an early and prominent role in the pathology of Alzheimer's disease (AD). Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) has been identified as a negative regulator of innate and adaptive immunity. However, whether TIPE2 affects cognitive functions in AD-like mouse models remains unknown. In this study, we compared the gene and protein expressions of TIPE2 between the APP/PS1 mice and the age-matched wild type (WT) mice at different stages of development using western blot and RT-qPCR. The hippocampal expression of the TIPE2 mRNA and protein in APP/PS1 mice was higher than that of the WT mice starting from 6 months to 10 months. However, the difference of the TIPE2 expression between the APP/PS1 mice and the WT mice declined in a time-dependent manner. The spatial learning and memory deficit from the 8-month-old APP/PS1 mice was observed in the Y-maze test and fear conditioning task. Interestingly, overexpression of TIPE2 by intra-hippocampal injection of AAV-TIPE2 into APP/PS1 mice resulted in an improvement of learning and memory and reduced expression of inflammatory cytokines, such as TNF-α, IL-6 and IL-1β, and increased expression of anti-inflammatory cytokines, such as IL-10 and Arg-1. Taken together, our findings show that the TIPE2 expression level was negatively correlated with the pathogenesis of Alzheimer's disease, and overexpression of TIPE2 attenuates cognitive deficits in APP/PS1 mice, suggesting TIPE2 is a potential target for pharmacological intervention and improvement of cognitive deficits. [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]

Objective To investigate the mRNA expression of tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2), Foxp3 (a functional molecule for regulatory T cells), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) in peripheral blood mononuclear cells (PBMCs) in patients with chronic hepatitis C (CHC) and their clinical significance. Methods A total of 80 CHC patients who were hospitalized in The Third Hospital of Hebei Medical University from May 2012 to December 2016 and did not receive antiviral drugs or immunoregulatory drugs were enrolled as CHC group, and 45 healthy volunteers were enrolled as controls. Quantitative real-time PCR was used to measure the mRNA expression of TIPE2, Foxp3, and CTLA-4 in PBMCs; the correlation between liver biochemical parameters and HCV RNA was observed, as well as the influence of TIPE2 on Foxp3 and CTLA-4. The t-test was used for comparison of continuous data between two groups, the chi-square test was used for comparison of categorical data between two groups, and Pearson correlation was used for correlation analysis. Results Compared with the healthy control group, the CHC group had a significant reduction in the mRNA expression of TIPE2 (0.564±0.232 vs 0.704±0.165, t=3.569, P＜0.001) and significant increases in the mRNA expression of Foxp3 (0.701±0.405 vs 0.527±0.184, t=2.725, P=0.007) and CTLA-4 (0.638±0.211 vs 0.448±0.134, t=5.449, P＜0.001). The mRNA expression of TIPE2 was negatively correlated with serum alanine aminotransferase (r=-0.368, P=0.001), aspartate aminotransferase (r=-0.417, P＜0.001), total bilirubin (r=-0.416, P＜0.001), and HCV RNA load (r=-0.327, P=0.003) and was positively correlated with the mRNA expression of Foxp3 (r=0.461, P＜0.001) and CTLA-4 (r=0.257, P=0.021). The mRNA expression of Foxp3 was negatively correlated with total bilirubin(r=-0.284,P=0.011). Conclusion CHC patients have abnormalities in the mRNA expression of TIPE2 and the mRNA expression and function of Foxp3 and CTLA-4, which is associated with the degree of hepatocellular injury and viral replication. The TIPE2 gene may be involved in the pathogenesis of CHC by positively regulating immune response mediated by regulatory T cells. [ABSTRACT FROM AUTHOR]

Abstract Aims The tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2) participates in multiple inflammatory diseases. However, its underlying mechanism in osteoporosis has not been elucidated. The aim of current study is to preliminarily clarify the function of TIPE2 in the pathogenesis of osteoporosis. Main methods TIPE2 expression in patients with osteoporosis was measured by Western blot and qRT-PCR methods. Proinflammatory cytokines including TNF-α, IL-1 and IL-6 were assessed via enzyme-linked immunosorbent assay. Serum fasting PINP and β-CTX were measured by the chemiluminescence method. Simple logistic regression analysis was performed for the odds ratio (OR) for TIPE2. Key findings TIPE2 expression in patients with osteoporosis was dramatically decreased and negatively correlated with proinflammatory cytokines. Furthermore, TIPE2 level was negatively correlated with fasting β-CTX, but not PINP, indicating that TIPE2 participates in the pathogenesis of osteoporosis dominantly by supression of bone resorption. Interestingly, TIPE2 expression level was positively correlated with bone mineral density (BMD), and its expression level can predict the risk of bone fracture using the simple logistic regression assay. Significance Our findings clarify that TIPE2 alleviates the pathogenesis of osteoporosis by suppressing the inflammatory status and the ability of TIPE2 for predicts bone fracture further demonstrated that TIPE2 might serve as a novel diagnostic marker and a therapeutic target for osteoporosis. [ABSTRACT FROM AUTHOR]