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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.)

TNF-α-inducible protein 8-like 2 (TIPE2) is a recently discovered regulator of inflammation that can maintain immune homeostasis, exerting a significant role in the development of inflammation-related diseases. Here, we aimed to explore the role and potential regulatory mechanism of TIPE2 in the progression of inflammatory pain. In the present study, a mouse BV2 microglia cell activation-mediated inflammatory model was developed with LPS induction, and a mouse inflammatory pain model was established with complete Freund's adjuvant (CFA) injection. In vitro, the TIPE2 expression was decreased in LPS-induced BV2 cells. Overexpression of TIPE2 mitigated LPS-medicated microglial activation via decreasing nitric oxide (NO) generation and the expression of microglia marker IBA-1. Notably, increasing TIPE2 expression alleviated microglial activation-triggered expression levels and releases of proinflammatory factors such as TNF-α, IL-1β, and IL-6. Mechanism analysis verified that overexpression of TIPE2 blunted Rac1-mediated activation of NF-κB pathway following LPS stimulation. More importantly, CFA injection reduced the expression of TIPE2 in a mouse inflammatory pain model and overexpression of TIPE2 alleviated CFA-mediated pain hypersensitivity and inflammatory response, and inactivated microglia cell in vivo. Furthermore, overexpression of TIPE2 decreased Rac1 expression and suppressed the activation of NF-κB pathway in spinal cord after CFA injection. In summary, the present study revealed that overexpression of TIPE2 mitigated inflammatory pain through suppressing microglial activation-induced inflammation by inactivating Rac1/NF-κB pathway. The study provides a novel theoretical foundation for the therapy of inflammatory pain., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., Competing Interests: Disclosure All authors declare that there are no competing interests., (Copyright © 2019. Published by Elsevier B.V.)

Childhood asthma, an airway inflammatory disease, is a serious threat to the child's quality of life. Recently, TIPE2 expression was reported to be decreased in children with asthma. Therefore, additional studies focusing on TIPE2 might provide an approach for treating childhood asthma. In this study, we found that TIPE2 was poorly expressed in hyperstretched human bronchial epithelial cells (BEAS-2B). TIPE2 overexpression also significantly suppressed the stretch-induced secretion of asthma-related inflammatory factors (TNF-α, TSLP, MMP-9, and VEGF). In contrast, TIPE2 inhibition significantly promoted the secretion of TNF-α, TSLP, MMP-9, and VEGF. Furthermore, overexpression of TIPE2 remarkably inhibited the activation of Wnt/β-catenin in hyperstretched BEAS-2B cells, while siTIPE2 activated Wnt/β-catenin in hyperstretched BEAS-2B cells. Further analysis showed that the Wnt/β-catenin signal inhibitor Dkk-1 could further enhance the TIPE2-induced suppression of Wnt/β-catenin signaling, which also suppressed the siTIPE2-induced secretion of TNF-α, TSLP, MMP-9, and VEGF in hyperstretched BEAS-2B cells. Dkk-1 reversed the effects of siRNA-TIPE2 on Wnt/β-catenin signaling and inflammatory cytokines. In summary, we have exhibited that TIPE2 inhibited the expression of asthma-related inflammatory factors in hyperstretched BEAS-2B cells by suppressing the Wnt/β-catenin signaling pathway. TIPE2 may be involved in airway inflammation during asthma attack, and it may be used as a potential therapeutic target for bronchial epithelial inflammation in childhood asthma.

AbstractBackgroundMethodsResultsConclusionsColon cancer (CC) is the main fatal disease of humans. Microwave hyperthermia (MH) is an adjuvant therapy for diverse cancers. Tumor necrosis factor-α induced protein-8-like 2 (TIPE2) is a tumor suppressor. However, the effect of MH combined with TIPE2 on CC remains unclear.The orthotopic CC mouse model was constructed by mouse CC CT26-Luc cells, and mice were randomized into control, model (CT26-Luc), CT26-Luc + Vector, CT26-Luc + TIPE2, CT26-Luc + MH, and CT26-Luc + MH+TIPE2 groups (n = 6). Tumor growth pretreatment and post-treatment by in vivo fluorescence image analysis was detected. TIPE2 expression and cell transfection efficiency was detected by qRT-PCR and western blot. The pathological changes by HE staining, apoptosis by TUNEL staining, serum inflammatory factors by ELISA, TIPE2 expression by immunohistochemistry, and NF-κB signaling by western blot was performed.Paracancerous tissues showed higher TIPE2 expression than in CC tissues. CT26-Luc + TIPE2, CT26-Luc + MH, and CT26-Luc + MH+TIPE2 groups reduced tumor growth, tumor cell infiltration, and increased apoptosis. CT26-Luc + TIPE2 group had lower NF-κB, TNF-α, IL-1β, IL-6, p-p65, and p-IKK expression, and elevated TIPE2 and IkB expression, which was reversed by CT26-Luc + MH group. Moreover, CT26-Luc+MH+TIPE2 group showed opposite effects on the above factor expression of CT26-Luc+MH group.Combination of MH with TIPE2 could impede CC tumor growth, providing scientific bases for its clinical application in CC treatment. [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]

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: 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]

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]

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]

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

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.

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]

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]

• 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]

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]

The purpose of the present study was to investigate the possible role of TIPE2 on acute lung injury (ALI) induced by myocardial ischemia/reperfusion (MIR) in diabetic rats. Sprague-Dawley (SD) rats were randomly separated into four groups: control+sham (C + sham); control+MIR (C + MIR); diabetes+sham (D + sham); diabetes+MIR (D + MIR). Diabetes was induced using streptozotocin. Eight weeks after diabetes induction, MIR was conducted. At 2 h after MIR, myocardial injury indices were assessed; arterial blood, bronchoalveolar lavage fluid (BALF) and lung tissues were collected for corresponding detection. Rats subjected to MIR showed serious ALI (estimated via pathological changes, lung injury score and Wet/Dry weight ratio), lung inflammation and pulmonary cell apoptosis compared with sham groups, especially in D + MIR group. Evaluation of protein expression in lung tissues showed that p-JNK and nuclear NF-κB p65 protein levels were higher in D + MIR group as compared with C + MIR group. Besides, either hyperglycemia or MIR can significantly upregulate TIPE2 protein levels. In conclusion, diabetic lungs are more susceptible to MIR. TIPE2 may involve in this pathological process, possibly through regulation of inflammation, oxidative stress and apoptosis. • Diabetic rats subjected to MIR showed aggravated ALI • TIPE2 were upregulated either after STZ injection or MIR • TIPE2 may have protective effect on MIR-induced ALI in Diabetic rats • TIPE2 negatively regulates inflammation, oxidative stress, apoptosis, NF-κB and JNK pathways that involved in MIR-induced ALI [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]