Expression Of Tumor Necrosis Factor-α-induced Protein 8-like 2 Research Articles

Tumor necrosis factor-α-induced protein 8-like 2 alleviates morphine antinociceptive tolerance through reduction of ROS-mediated apoptosis and MAPK/NF-κB signaling pathways

Chronic morphine tolerance is a repulsive barrier to the clinical treatment of pain. Whereas the underlying molecular mechanisms of morphine tolerance remain unknown. Here, we proposed that tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is an essential control point regarding the progression of chronic morphine antinociceptive tolerance. We found that TIPE2 levels in the lumbar spinal cord were significantly downregulated in the morphine tolerance mouse model. Specifically, decreased TIPE2 by morphine tolerance was primarily expressed in spinal neurons, while increased expression of spinal TIPE2 distinctly attenuated the chronic morphine antinociceptive tolerance and tolerance-associated hyperalgesia. We also observed that increased expression of spinal TIPE2 significantly reduced morphine tolerance-induced neuronal ROS production and apoptosis, along with the activation of MAPKs and NF-κB signaling pathways. Moreover, the increased TIPE2 expression inhibited neuronal activation and glial reactivity in the spinal dorsal horn after chronic morphine exposure. Additionally, TIPE2 overexpression in cultured SH-SY5Y cells significantly suppressed ROS production and apoptosis in response to morphine challenge. Therefore, we can conclude that the upregulation of spinal TIPE2 may attenuate the morphine antinociceptive tolerance via TIPE2-dependent downregulation of neuronal ROS, inhibition of neuronal apoptosis, suppression of MAPKs and NF-κB activation. TIPE2 may be a potential strategy for preventing morphine tolerance in the future studies and clinical settings.

Tumor Necrosis Factor-α-Induced Protein 8-Like 2 Negatively Regulates Innate Immunity Against RNA Virus by Targeting RIG-I in Macrophages.

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.

Changes in expressions of TIPE2 and TF in peripheral blood mononuclear cells of patients with acute exacerbation of bronchial asthma and their associations with changes in inflammatory factors and T lymphocytes.

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. 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. Compared with those in Control group, the proportion of eosinophils and FeNO 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. 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.

TIPE2 specifies the functional polarization of myeloid-derived suppressor cells during tumorigenesis.

Myeloid-derived suppressor cells (MDSCs) are "polarized" myeloid cells that effectively promote tumorigenesis by inhibiting antitumor immunity. How myeloid cells acquire the protumoral properties during tumorigenesis is poorly understood. We report here that the polarity protein TIPE2 (tumor necrosis factor-α-induced protein 8-like 2) mediates the functional polarization of murine and human MDSCs by specifying their pro- and antitumoral properties. Tumor cells induced the expression of TIPE2 in Gr1+CD11b+ cells through reactive oxygen species (ROS). TIPE2 in turn increased the expression of protumoral mediators such as CCAAT/enhancer-binding protein-β while inhibiting the expression of antitumoral mediators. Consequently, tumor growth in TIPE2-deficient mice was significantly diminished, and TIPE2-deficient MDSCs markedly inhibited tumor growth upon adoptive transfer. Pharmaceutical blockade of ROS inhibited TIPE2 expression in MDSCs and reduced tumor growth in mice. These findings indicate that TIPE2 plays a key role in the functional polarization of MDSCs and represents a new therapeutic target for cancer immunotherapy.

Role of TIPE2 in pyroptosis in macrophage of mice: evaluation using siRNA technique

Objective To evaluate the role of tumor necrosis factor α-induced protein 8-like-2 (TIPE2) in pyroptosis in macrophage of mice using small interfering RNA (siRNA) technique. Methods J774A.1 macrophages of mice were divided into 4 groups (n=6 each) using a random number table method: non-specific siRNA (Scr-siRNA) group (S group), Scr-siRNA plus LPS/ATP group (S+ LPS/ATP group), TIPE2-siRNA group (T group) and TIPE2-siRNA plus LPS/ATP group (T+ LPS/ATP group). The corresponding siRNA and Lipofectamine2000 transfection reagents were added to each group, and transfection was performed for 24-48 h, and in addition LPS 1.0 μg/ml was then added, cells were incubated for 5 h, then ATP 5.0 mmol/L was added, and cells were incubated for 1 h in S+ LPS/ATP and T+ LPS/ATP groups.Cells were collected to detect the expression of TIPE2, NOD-like receptor familypyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and Gasdermin D (GSDMD) (by Western blot). The supernatant was collected for determination of lactic dehydrogenase (LDH) activity and concentrations of interleukin-1beta (IL-1β) and IL-18 (by enzyme-linked immunosorbent assay). Results Compared with group S, the expression of TIPE2 was significantly down-regulated, the expression of NLRP3, caspase-1, ASC and GSDMD was up-regulated, and the LDH activity and concentrations of IL-1β and IL-18 in supernatant were increased in group S+ LPS/ATP (P<0.05). Compared with group T, the expression of TIPE2 was significantly down-regulated, the expression of NLRP3, caspase-1, ASC and GSDMD was up-regulated, and the LDH activity and concentrations of IL-1β and IL-18 in supernatant were increased in group T+ LPS/ATP (P<0.05). Compared with group S+ LPS/ATP, the expression of TIPE2 was significantly down-regulated, the expression of NLRP3, caspase-1, ASC and GSDMD was up-regulated, and the LDH activity and concentrations of IL-1β and IL-18 in supernatant were increased in group T+ LPS/ATP (P<0.05). Conclusion Application of siRNA technique once again confirms that TIPE2 can inhibit pyroptosis in macrophages of mice. Key words: Pyroptosis; Macrophages; TIPE2

Correlation of serum levels and gene expression of tumor necrosis factor-α-induced protein-8 like-2 with Parkinson disease severity.

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

TIPE2 inhibits GC via regulation of cell proliferation, apoptosis and inflammation.

Gastric cancer (GC), a type of gastric mucosal epithelium disease caused by common malignant tumors, has become a major threat to human health and survival. Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) is a negative immune regulatory factor that is selectively expressed in immune organs, immune cells and various epithelial cells and serves an important role in the maintenance of human physiological immune homeostasis. In our preliminary study, we found that the expression of TIPE2 was downregulated or absent in GC tissues compared with normal gastric mucosa tissues, indicating that TIPE2 may play a significant role in the development of GC. To clarify the role of TIPE2 in the progression of human GC and to elucidate the underlying mechanism, the association between TIPE2 and phosphatidylinositol 3-kinase (PI3K)/AKT, the cell cycle, the caspase-related apoptosis pathway and the NF-κB signaling pathway were investigated through western blot and flow cytometric analysis. It was determined that TIPE2 inhibited GC cell proliferation mainly by reducing the expression of phosphorylated AKT and ERK, which caused subsequent inhibition of the PI3K-AKT and Ras-Raf-MEK-ERK1/2 signaling pathways. Additionally, we investigated the relationship between TIPE2 and GC and discovered that TIPE2 inhibited tumor progression via growth, apoptosis and inflammatory pathways. The results of the present study provided a theoretical basis for the development and application of TIPE2 as an antitumor agent.

Tumor necrosis factor-α-induced protein 8-like-2 is involved in the activation of macrophages by Astragalus polysaccharides invitro.

In previous years, studies have shown that Astragalus polysaccharides (APS) can improve cellular immunity and humoral immune function, which has become a focus of investigations. Tumor necrosis factor‑α‑induced protein 8‑like2 (TIPE2) is a negative regulator of immune reactions. However, the effect and underlying mechanisms of TIPE2 on the APS‑induced immune response remains to be fully elucidated. The present study aimed to examine the role of TIPE2 and its underlying mechanisms in the APS‑induced immune response. The production of nitric oxide (NO) was detected in macrophages invitro following APS stimulation. In addition, the present study interfered with the expression of TIPE2 in macrophages, and examined the production of cytokines, NO and components of the mitogen‑activate protein kinase (MAPK) signaling pathway following APS stimulation. The results showed that APS was able to activate macrophages by inducing the production of interleukin (IL)‑1β, tumor necrosis factor (TNF)‑α, IL‑6 and NO. Furthermore, RAW264.7 cells were stimulated with APS when TIPE2 was silenced, and it was found that the production of TNF‑α, IL‑6, IL‑1β and NO were upregulated, and the signaling pathway of MAPK was activated. Taken together, these results demonstrated that TIPE2 had an important negative effect on the APS‑induced production of inflammatory cytokines and NO via the MAPK signaling pathway.

TIPE2 negatively regulates mycoplasma pneumonia-triggered immune response via MAPK signaling pathway

Excessive immune responses played an important role in pathophysiology of mycoplasma pneumonia (MP) infection. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a negative regulator of immune response. This study investigated the expression change of TIPE2 and its role in immune defense against MP infection, as well as the underlying mechanisms. Expressions of TIPE2 both in patients and in macrophages in vitro after MP infection were measured. We further studied cytokine production and mitogen-activated protein kinase (MAPK) signaling function in macrophages with interfered expression of TIPE2 upon MP infection. A significant decrease of TIPE2 mRNA expression was observed in peripheral blood mononuclear cells (PBMCs) from MP patients, which was correlated with the severity of infection. Accordingly we found down-regulation of TIPE2 expression in macrophages after MP infection. In vitro study further suggested that TIPE2 jeopardized inflammatory cytokine production trigged by MP infection via inhibiting MAPK signaling pathway. These findings provided evidences of the novel function of TIPE2 in anti-MP immunity and its possible clinical utility related clinical significance.

Increased expression of TIPE2 in alternatively activated macrophages is associated with eosinophilic inflammation and disease severity in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial disorder characterized by exaggerated local immune responses. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a novel protein with potential immune modulating function. The expression and function of TIPE2 in human airway diseases are unclear. The expression of TIPE2 in sinonasal mucosal samples was assessed by means of quantitative reverse transcript-polymerse chain reaction, immunohistochemistry, and Western blotting. The human monocytic/macrophage cell line, THP-1 cells, was stimulated with various cytokines. Computed tomography (CT) scan images, endoscopic findings, and symptoms were scored. Compared with non-eosinophilic polyps and control mucosa, the mRNA and protein expression of TIPE2 was significantly upregulated in eosinophilic polyps, with a further increase in those with asthma. The number of CD68+ CD163+ alternatively activated (M2) macrophages was increased in eosinophilic polyps. TIPE2 was mainly expressed by M2 macrophages in sinonasal mucosa and its expression was upregulated in M2 macrophages in eosinophilic polyps. Interleukin (IL)-4 and IL-13, but not interferon (IFN)-γ or IL-17A, induced TIPE2 expression in differentiated THP-1 cells. The mRNA levels of IL-4 and IL-13 correlated with the mRNA levels of TIPE2 and M2 macrophage markers in sinonasal mucosa. Importantly, the number of TIPE2+ cells, particularly TIPE2+ CD163+ CD68+ M2 macrophages, correlated positively with the number of eosinophils and total inflammatory cells in sinonasal mucosa, as well as disease duration, CT scores, hyposmia scores, and polyp size in CRSwNP. The T-helper 2 milieu is able to induce TIPE2 expression in macrophages. TIPE2-positive M2 macrophages potentially contribute to eosinophilic inflammation and disease progression in CRSwNP.

Stable silencing of TIPE2 reduced the PolyI:C‑induced apoptosis in THP‑1 cells.

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

Increased expression of TIPE2 mRNA in PBMCs of patients with ankylosing spondylitis is negatively associated with the disease severity

Ankylosing spondylitis (AS) is an autoimmune disease and characterized by chronic inflammatory arthritis. Tumor necrosis factor α induced protein-8 like-2 (TIPE2) is responsible for maintaining immune homeostasis by inhibiting the secretion of inflammatory cytokines in the condition of inflammation. However, whether TIPE2 participates in the development of AS remains unknown. In this study, we measured the mRNA expression of TIPE2 and TIPE1 in peripheral blood mononuclear cells (PBMCs) from 45 AS patients and 40 healthy controls by qRT-PCR. The results showed TIPE2 expression was significantly increased in AS patients compared with controls (P=0.0066), while there was no significant difference for TIPE1 between two groups (P=0.2302). Moreover, the expression of TIPE2 mRNA in AS patients were decreased after treatment with TNF-α blocker (P<0.001). In addition, we found that TNF-α or plasma from AS patients induced TIPE2 expression in THP-1 cells in vitro. More importantly, the TIPE2 mRNA expression levels were negatively correlated with TNF-α, hsCRP and bath ankylosing spondylitis disease activity index (BASDAI) (r=−0.3574, P=0.0159; r=−0.3174, P=0.0336; r=−0.6000, P<0.0001; respectively) in the AS patients. These results indicated that TIPE2 contributes to the pathogenesis of AS.

TIPE2 suppresses the tumorigenesis, growth and metastasis of breast cancer via inhibition of the AKT and p38 signaling pathways.

Breast cancer is the second leading cause of cancer‑related deaths in female patients, and the main reasons are late diagnosis, limited therapeutic options and metastasis. Therefore, development of molecular therapeutic targets for breast cancer to suppress tumorigenesis, growth and metastasis may improve the therapeutic options and be of great benefit to patients. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a novel molecule for maintaining immune homeostasis and is involved in cancer development. Previous studies have shown that TIPE2 plays a suppressive role in the development of several types of human cancers. However, its role in breast cancer is still not clear. In the present study, we detected TIPE2 expression in human breast cancer and adjacent normal tissues. The expression of TIPE2 was reduced in breast cancer tissues compared to the level in adjacent normal tissues. We then established a breast cancer cell line stably expressing TIPE2 to investigate the role of TIPE2 in breast cancer carcinogenesis. Our results showed that overexpression of TIPE2 significantly inhibited the proliferation of MDA-MB‑231 cells as detected by Cell Counting Kit-8 assay and suppressed the migration and invasion of breast cancer cells as detected by Transwell migration and invasion assays invitro. TIPE2 also promoted cell apoptosis as detected by flow cytometry analysis. Moreover, TIPE2 inhibited the tumorigenesis of breast cancer invivo. Mechanistically, TIPE2 inhibited the phosphorylation of AKT and p38 as detected by western blot analysis. Taken together, TIPE2 suppressed breast cancer tumorigenesis, growth and metastasis possibly via regulation of the AKT and p38 signaling pathways. The results indicate that TIPE2 may be a potential therapeutic target for breast cancer therapy.

Hepatitis C virus promotes hepatocellular carcinogenesis by targeting TIPE2, a new regulator of DNA damage response.

Infection of hepatitis C virus (HCV) is associated with primary hepatocellular carcinoma (HCC). However, its underlying molecular mechanisms remain enigmatic. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2), a new negative regulator of immunity, plays significant roles in modulating inflammation and tumorigenesis. We hypothesized that TIPE2 might be involved in the development of HCV-induced HCC. To test this hypothesis, the expression of TIPE2 was determined by Western blot in the tumor and pericarcinomatous tissues collected from ten HCV-positive HCC patients; the interaction between TIPE2 and HCV-encoded non-structural proteins was analyzed by immunoprecipitation and immunofluorescence assays, and tumorigenesis and its mechanisms were studied in cell models and nude mice. Our results demonstrated that the expression of TIPE2 was significantly reduced in HCC tissues compared to that in the paracarcinoma tissues. HCV-encoded non-structural protein NS5A could specifically interact with TIPE2 and induce its degradation. Downregulation of TIPE2 by shRNA in cell lines increased genomic DNA damage and promoted cell colony formation in vitro and tumorigenesis in nude mice. In contrast, overexpression of TIPE2 had an opposite effect. Downregulation of TIPE2 by NS5A is associated with genomic DNA instability and HCV-induced HCC development. Thus, TIPE2 may be a new therapeutic target for the treatment of HCV-associated HCC.

TIPE2, a negative regulator of TLR signaling, regulates p27 through IRF4-induced signaling.

Targeted inhibition of specific toll-like receptor (TLR) pathways may provide an effective strategy to prevent the development of selected gastric malignancies. Tumor necrosis factor (TNF)-α-induced protein 8-like-2 (TIPE2) was identified as a novel negative regulator of TLR signaling. Our previous study identified TIPE2 as an inhibitor of gastric cancer cell growth; it promotes p27 expression, which leads to restored control of the cell cycle and cell division. However, the molecular mechanism by which TIPE2 regulates p27 remains unclear. In the present study, we examined the expression patterns of TIPE2 in serial clinical gastritis tissues as well as gastric cancer, and found a negative correlation between TIPE2 expression and progression of gastritis to gastric cancer. This negative correlation verified the role of TIPE2 in preventing the occurrence and development of gastric cancer, suggesting that TIPE2 may be a potential biomarker for gastric cancer progression. To determine the mechanism employed by TIPE2 in gastric cell carcinogenesis, a TIPE2-expressing plasmid was introduced into gastric cell lines, and microarray and western blot analysis revealed that TIPE2 selectively upregulates the expression of interferon regulatory factor 4 (IRF4). Variations in IRF4 expression were additionally verified in knockout mice. Next, the effect of IRF4 on p27 expression was tested by an IRF4 siRNA interference assay. Finally, we explored the signaling pathways used by TIPE2 to regulate IRF4. An experiment using pathway inhibitors and a nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) luciferase reporter assay showed that NF-κB plays a crucial role in regulating IRF4 expression. Our data provide evidence that TIPE2, a potential biomarker for gastric cancer progression, stimulates an IRF4-associated signaling cascade that promotes p27 expression and controls cell growth. To the best of our knowledge, this is the first study to demonstrate that IRF4 acts as an inhibitor of epithelial cell proliferation and mediates the expression of TIPE2, a negative regulator of TLR signaling, to control cell growth.

The Effect of Tumor Necrosis Factor-α-Induced Protein 8 Like-2 on Immune Response of CD4+T Lymphocytes in Mice after Thermal Injury

The status of cellular immunity has been shown to be associated with the occurrence and development of sepsis. Accumulating evidence has demonstrated that tumor necrosis factor-α-induced protein 8 like-2 (TIPE2) plays an important role in maintaining homeostasis of immune function. The present study, with the use of a controlled in vivo approach, demonstrated the effect of TIPE2 on cell-mediated immunity of CD4+ T lymphocytes in thermal injury murine model. One hundred and twenty-eight male mice were randomly allocated into four groups, which were sham burn group (n=48), burn group (n=48), burn with lentivirus-RNAi-TIPE2 transfection group (n=16), burn with negative control transfection group (n=16), and they were sacrificed at the designated time points. CD4+ T lymphocytes were isolated from the spleen using MACS microbeads. Phenotypes were analyzed by flow cytometry analysis, and cytokines were determined using ELISA kits. We found that the expression of TIPE2 was markedly increased in CD4+T lymphocytes in mice at 24,48 and 72 hours postburn. Down-regulation of TIPE2 by lentivirus-RNAi-TIPE2 attenuated the suppressive effect of CD4+T lymphocytes, which was associated with profound elevation of nuclear factor of activated T cell (NF-AT) activity. These results demonstrate that TIPE2 appear to be involved in the immune regulation of CD4+ T lymphocytes, and the decrease in TIPE2 expression on CD4+T lymphocytes in vivo can enhance peripheral T lymphocyte function after thermal injury. These data might provide a valid strategy to prevent the development of immunosuppressive state resulted from major burns.