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Cell death is indispensable in the physiology, pathology, growth, development, senility and death of an organism. In recent years, the identification of a highly regulated form of necrosis, known as necroptosis, has challenged the traditional concept of necrosis and apoptosis, which are two major modes of cell death. This novel manner of cell death is similar in form to necrosis in terms of morphological features, and it can also be regulated in a caspase-independent manner. Therefore, necroptosis can be understood initially as a combination of necrosis and apoptosis. The mechanism of its regulation, induction and inhibition is complicated, and involves a range of molecular expression and regulation. According to the recent literature, necroptosis takes place in the physiological regulatory processes of an organism and is involved in the occurrence, development and prognosis of a variety of diseases that have a necrosis phenotype, including neurodegenerative diseases, ischemic disease, hemorrhagic disease, inflammation and viral infectious diseases. In the present review, the features, molecular mechanism and identification of necroptosis under pathological conditions are discussed, with particular emphasis on its association with stroke.

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

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

Background Exosomes as the main therapeutic vectors of mesenchymal stem cells (MSC) for inflammatory bowel disease (IBD) treatment and its mechanism remain unexplored. Tumor necrosis factor-α stimulated gene 6 (TSG-6) is a glycoprotein secreted by MSC with the capacities of tissue repair and immune regulation. This study aimed to explore whether TSG-6 is a potential molecular target of exosomes derived from MSCs (MSCs-Exo) exerting its therapeutic effect against colon inflammation and repairing mucosal tissue. Methods Two separate dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced IBD mouse models were intraperitoneally administered MSCs-Exo extracted from human umbilical cord MSC (hUC-MSC) culture supernatant. Effects of MSCs-Exo on intestinal inflammation, colon barrier function, and proportion of T cells were investigated. We explored the effects of MSCs-Exo on the intestinal barrier and immune response with TSG-6 knockdown. Moreover, recombinant human TSG-6 (rhTSG-6) was administered exogenously and colon inflammation severity in mice was evaluated. Results Intraperitoneal injection of MSCs-Exo significantly ameliorated IBD symptoms and reduced mortality rate. The protective effect of MSCs-Exo on intestinal barrier was demonstrated evidenced by the loss of goblet cells and intestinal mucosa permeability, thereby improving the destruction of tight junctions (TJ) structures and microvilli, as well as increasing the expression of TJ proteins. Microarray analysis revealed that MSCs-Exo administration downregulated the level of pro-inflammatory cytokines and upregulated the anti-inflammatory cytokine in colon tissue. MSCs-Exo also modulated the response of Th2 and Th17 cells in the mesenteric lymph nodes (MLN). Reversely, knockdown of TSG-6 abrogated the therapeutic effect of MSCs-Exo on mucosal barrier maintenance and immune regulation, whereas rhTSG-6 administration showed similar efficacy to that of MSCs-Exo. Conclusions Our findings suggested that MSCs-Exo protected against IBD through restoring mucosal barrier repair and intestinal immune homeostasis via TSG-6 in mice.

Understanding the mechanism of lymph node metastasis, a poor prognostic sign for prostate cancer, and the further dissemination of the disease is important to develop novel treatment strategies. Recent studies have reported that C‐C chemokine receptor 7 (CCR7), whose ligand is CCL21, is abundantly expressed in lymph node metastasis and promotes cancer progression. Tumor necrosis factor‐α (TNF‐α) is chronically produced at low levels within the tumor microenvironment. The aim of this study was to determine whether TNF‐α promotes prostate cancer dissemination from metastatic lymph nodes through activation of the CCL21/CCR7 axis. First, human prostate cancer cells were determined to express both TNF‐α and CCR7. Second, low concentrations of TNF‐α were confirmed to induce CCR7 in prostate cancer cells through phosphorylation of ERK. Finally, CCL21 was found to promote the migration of prostate cancer cells through phosphorylation of the protein kinase p38. Our results suggest that TNF‐α leads to the induction of CCR7 expression and that the CCL21/CCR7 axis might increase the metastatic potential of prostate cancer cells in lymph node metastasis. TNF‐α acts as a regulator of increased prostate cancer cell migration via upregulation of CCR7. Targeting TNF‐α and ultimately the CCL21/CCR7 axis my be a novel therapeutic strategy in prostate cancer.

We prepared three-dimensional (3-D) organoids of human stomach cancers and examined the correlation between the tumorigenicity and cytotoxicity of Helicobacter pylori (H. pylori). In addition, the effects of hepatoma-derived growth factor (HDGF) and tumor necrosis factor (TNFα) on the growth and invasion activity of H. pylori-infected gastric cancer organoids were examined. Cytotoxin-associated gene A (CagA)-green fluorescence protein (GFP)-labeled H. pylori was used to trace the infection in gastric organoids. The cytotoxicity of Cag encoded toxins from different species of H. pylori did not affect the proliferation of each H. pylori-infected cancer organoid. To clarify the role of HDGF and TNFα secreted from H. pylori-infected cancer organoids, we prepared recombinant HDGF and TNFα and measured the cytotoxicity and invasion of gastric cancer organoids. HDGF controlled the growth of each organoid in a species-specific manner of H. pylori, but TNFα decreased the cell viability in H. pylori-infected cancer organoids. Furthermore, HDGF controlled the invasion activity of H. pylori-infected cancer organoid in a species-dependent manner. However, TNFα decreased the invasion activities of most organoids. We found different signaling of cytotoxicity and invasion of human gastric organoids in response to HDGF and TNFα during infection by H. pylori. Recombinant HDGF and TNFα inhibited the development and invasion of H. pylori-infected gastric cancer differently. Thus, we propose that HDGF and TNFα are independent signals for development of H. pylori-infected gastric cancer. The signaling of growth factors in 3-D organoid culture systems is different from those in two-dimensional cancer cells.

Tumour necrosis factor‐α (TNF‐α) and transforming growth factor‐β1 (TGF‐β1) are peptides with multiple biological activities that influence neoplastic, immunologic and fibroproliferative diseases. There are clear interrelationships and overlap between the actions of TNF‐α and TGF‐β1 in lung fibrosis; therefore, we postulated that TNF‐α may play a significant role in regulating TGF‐β1 expression in lungs. We recently reported that TNF‐α activates the extracellular regulated kinase (ERK)‐specific pathway in fibroblasts resulting in stabilization of TGF‐β1 mRNA and increased expression of TGF‐β1. In the current study, we further investigated the molecular mechanisms involved in TNF‐α regulation of TGF‐β1 expression. Nuclear run‐on assays showed that treatment of Swiss 3T3 fibroblasts with TNF‐α increased transcription of the TGF‐β1 gene in an ERK independent manner. Pre‐treatment with the activator protein‐1 (AP‐1) inhibitor curcumin attenuated TNF‐α induced transcription of the TGF‐β1 gene. TNF‐α induced increased levels of c‐Jun and C‐Fos in the nucleus accompanied by phosphorylation of c‐Jun. In electrophoretic mobility shift assays, AP‐1 binding to an AP‐1 binding site found within the TGF‐β1 promoter was increased in nuclear extracts from Swiss 3T3 fibroblasts treated with TNF‐α. Together, these results suggest that TNF‐α induces expression and DNA binding of AP‐1 resulting in increased transcription of the TGF‐β1 gene. It is essential to know which transcription pathways are activated because of the wide distribution of TNF‐α and TGF‐β1, the general lack of effective treatments for fibroproliferative disease and the possibility that targeting the correct transcription factors could be palliative.

Although tumor necrosis factor alpha (TNF-α) is known to serve a critical role in the pathogenesis of inflammatory osteolysis, the exact mechanisms underlying the effects of TNF-α on osteoclast recruitment and differentiation remain unclear. To investigate the mechanisms by which TNF-α influences osteoclast differentiation, mouse bone marrow-derived macrophages (BMMs) were used as osteoclast precursors, and osteoclastogenesis was induced by macrophage colony-stimulating factor and receptor activator of nuclear factor (NF)-κB ligand (RANKL) with or without TNF-α for 4 days. Then, NF-κB was inhibited using the inhibitor, BAY 11-7082. The results indicated that treatment with TNF-α alone did not induce osteoclastogenesis of BMMs. However, TNF-α in combination with RANKL dramatically stimulated the differentiation of osteoclasts and positively regulated the expression of mRNA markers of osteoclasts. Finally, treatment of BMMs with BAY 11-7082 prevented the formation of mature osteoclasts by BMMs treated with TNF-α only or with RANKL, as well as the upregulation of osteoclast marker genes. Therefore, although TNF-α does not induce osteoclastogenesis alone, it does work with RANKL to induce osteoclastic differentiation, and the NF-κB pathway may serve an important role in this process.

Tumor necrosis factor (TNF) ligand related molecule 1A (TL1A), also termed TNF superfamily member 15 and vascular endothelial growth inhibitor is important for tumorigenicity and autoimmunity. However, the function of TL1A in diabetic retinopathy (DR) remains to be elucidated. The present study established a diabetes mellitus (DM) rat model to investigate TL1A, vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) expression levels in the retina, vitreous and serum of rats with DM at different stages (1 month group, 3 month group and 6 month group). The present study determined that TL1A expression levels in the retina and vitreous from the DM 1 month group were significantly lower compared with the control group. However, TL1A levels in the retina and vitreous were significantly increased in advanced stages of DM compared with the control group. Furthermore, the levels of VEGF in the retina and vitreous were significantly higher in the DM groups compared with the control group. The expression levels of TNF-α and IL-1β in the retina and vitreous were significantly higher in DM 3 month and 6 month groups compared with the control group. It is of note that the expression levels of TL1A were significantly lower in the DM 1 and 3 month groups compared with the control group; however, they were significantly increased in the DM 6 month group compared with the DM 3 month group. The expression levels of VEGF, TNF-α and IL-1β in blood serum have been observed to exhibit similar expression change dynamics as those of the retina and vitreous. Therefore, these findings suggest that TL1A may be a protective factor of DR, and may provide a rationale for the development of novel therapeutic strategies to treat DR.

Elevated levels of pro-inflammatory cytokines are consistently reported in schizophrenia (SZ) and bipolar-I disorder (BD), as well as among individuals who have been exposed to childhood trauma. However, higher levels of inflammatory markers in these disorders are yet to be investigated with respect to levels of exposure to different types of childhood trauma. Participants were 68 cases with a diagnosis of schizophrenia/schizoaffective disorder (SZ), 69 cases with a diagnosis of psychotic BD and 72 healthy controls (HC). Serum levels of interleukin 6 (IL-6), tumour necrosis factor-α (TNF-α) and C-reactive protein (CRP) were quantified, and childhood trauma exposure was assessed with the Childhood Trauma Questionnaire. The SZ group had significantly higher levels of IL-6, TNF-α and CRP when compared with the HC group (all p < 0.05, d = 0.41-0.63), as well as higher levels of TNF-α when compared with the BD group (p = 0.014, d = 0.50); there were no differences between the BD and HC groups for any markers. Exposure to sexual abuse was positively associated (standardised β = 0.326, t = 2.459, p = 0.018) with levels of CRP in the SZ group, but there were no significant associations between any form of trauma exposure and cytokine levels in the HC or BD groups. These results contribute to the evidence for a chronic state of inflammation in SZ but not BD cases. Differential associations between trauma exposure and levels of pro-inflammatory cytokines across the diagnostic categories suggest that trauma may impact biological (stress and immune) systems differently in these patient groups.