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Tumor Necrosis Factor-α (TNF-α) is a proinflammatory cytokine implicated in neuronal damage in response to cerebral ischemia. Ischemic preconditioning (IPC) provides neuroprotection against a subsequent severer or longer transient ischemia by ischemic tolerance. Here, we focused on the role of TNF-α in IPC-mediated neuroprotection against neuronal death following a subsequent longer transient cerebral ischemia (TCI). Gerbils used in this study were randomly assigned to eight groups; sham group, TCI operated group, IPC plus (+) sham group, IPC + TCI operated group, sham + etanercept (an inhibitor of TNF-a) group, TCI + etanercept group, IPC + sham + etanercept group, and IPC + TCI + etanercept group. IPC was induced by a 2-min sublethal transient ischemia, which was operated 1 day prior to a longer (5-min) TCI. A significant death of neurons was found in the stratum pyramidale (SP) in the CA1 area (CA1) of the hippocampus 5 days after TCI; however, IPC protected SP neurons from TCI. We found that TNF-α immunoreactivity was significantly increased in CA1 pyramidal neurons in the TCI and IPC + TCI groups compared to the sham group. TNF-R1 expression in CA1 pyramidal neurons of the TCI group was also increased 1 and 2 days after TCI; however, in the IPC + TCI group, TNF-R1 expression was significantly lower than that in the TCI group. On the other hand, we did not detect TNF-R2 immunoreactivity in CA1 pyramidal neurons 1 and 2 days after TCI; meanwhile, in the IPC + TCI group, TNF-R2 expression was significantly increased compared to TNF-R2 expression at 1 and 2 days after TCI. In addition, in this group, TNF-R2 was newly expressed in pericytes, which are important cells in the blood brain barrier, from 1 day after TCI. When we treated etanercept to the IPC + TCI group, IPC-induced neuroprotection was significantly weakened. In brief, this study indicates that IPC confers neuroprotection against TCI by TNF-α signaling through TNF-R2 and suggests that the enhancement of TNF-R2 expression by IPC may be a legitimate strategy for a therapeutic intervention of TCI. [ABSTRACT FROM AUTHOR]

Dietary polyunsaturated fatty acids (PUFA) and inflammatory proteins associate with immune activation and have been implicated in the pathophysiology of mood disorders. We have previously reported that individuals with bipolar disorder (BPD) have decreased PUFA intake, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA); and decreased PUFA concentration of plasma EPA and linoleic acid (LA). We have also reported an association between plasma LA and its metabolites and burden of disease measures in BPD. In the current cross-sectional study we collected blood samples and diet records from both bipolar (n = 91) and control subjects (n = 75) to quantify plasma cytokine concentrations and dietary LA intake, respectively. Using multiple linear regression techniques, we tested for case control differences in plasma cytokine levels and associations between cytokines and dietary LA intake, adjusting for sex, age, BMI, and total energy intake. We found significantly higher plasma levels of interleukin 18 (IL-18) (p = 0.036), IL-18 binding protein (IL-18BP) (p = 0.001), soluble tumor necrosis factor receptor (sTNFR) 1 (p = 0.006), and sTNFR2 (p = 0.007) in BPD compared with controls. Moreover, BPD significantly moderated the associations of dietary LA intake with plasma levels of IL-18, sTNFR1 and sTNFR2, which were inverse associations in bipolar individuals and positive associations in controls (p for dietary LA x BPD diagnosis interaction < 0.05 for all three). These findings suggest potential dysregulation of LA metabolism in BPD, which may extend to a modified influence of dietary LA on specific inflammatory pathways in individuals with BPD compared to healthy controls. [ABSTRACT FROM AUTHOR]

The transcription factor nuclear factor-κB (NF-κB) is a critical regulator of the immune response, inflammation, cell growth, and survival. Canonical and non-canonical pathways, two NF-κB pathways, are activated through diverse stimulators and receptors. NF-κB activity is dysregulated in various inflammation-related diseases and cancers. It was found that the persistent NF-κB activity has a major role in proliferation, apoptosis inhibition, metastasis, and cell cycle disruption in cancer cells and also the survival of cancer stem cells (CSCs) within the tumors. Therefore, suppression of the NF-κB pathway could be a promising therapeutic target for cancer therapy. Different biological inhibitors (e.g., peptides, small molecules, antisense oligonucleotides (ASOs), and antibodies (Abs)) have been demonstrated to inhibit the NF-κB pathway. Low stability in the circulation system, weak availability, and poor cellular uptake of some inhibitors limit their therapeutic applications. To address these drawbacks nanocarrier systems are often formulated and applied in drug delivery as an effective therapeutic approach. Targeted nanosystems (i.e., small molecules, peptides, Abs and Aptamers (Aps) conjugated nanocarriers), as well as smart responsive nanocarriers, can improve the efficiency of therapeutics while reducing the off-target toxicity. This review describes the NF-κB signaling pathways and mechanisms of their over-activation in tumor initiation and progression. The NF-κB inhibitors and their clinical applications are also discussed. It also overviews different nanocarriers used as robust vehicles for the delivery of NF-κB inhibitors and anti-tumor agents to improve the bioavailability of drugs and selective targeting of cancer cells to repress NF-κB activity in tumor cells. [Display omitted] • Nuclear factor-κB (NF-κB) is a critical regulator of the immune response, inflammation, cell growth, and survival. • The role of the NF-κB pathway in chronic inflammation and tumorigenesis has been approved. • Various inhibitors of the NF-κB pathway against cancers are used in clinical trials. • Advanced nanosystems are designed for targeted inhibition of the NF-κB pathway in cancers. • The future trends in the inhibition of the NF-κB illustrate the potential of advanced nanosystems for cancer therapy. [ABSTRACT FROM AUTHOR]

Ginsenoside metabolite compound K (CK), metabolite of the ginsenoside, is considered to exert numerous pharmacological efficacies of ginsenoside, including anti-inflammation and immunoregulatory effects. Rheumatoid arthritis (RA) is a multi-systemic autoimmune disease characterized by hyperplastic synovial membrane and systemic inflammation, which ultimately lead to progressive destructive inflammatory arthropathy. To evaluate the potential joint-protective effects of CK and the underlying mechanism, adjuvant arthritis (AA) was induced by complete Freund’s adjuvant in rats. After the onset of arthritis, The effect of CK on AA rats was evaluated by histopathology of the joint. The proliferation of fibroblast-like synoviocyte(FLS) was assayed by the Cell Counting Kit-8.The migration of FLS was assayed by transwell migration assay. Cytokines in the supernatant from FLS were measured by ELISA kit. Expression of Tumor Necrosis Factor Receptor Type 1(TNFR1) and Tumor Necrosis Factor Receptor Type 2(TNFR2) were detected by immunostaining analysis and western blot analysis. CK (80 mg/kg) significantly ameliorated the histopathological change of joint in AA rats, balanced the RANKL/OPG ratio and attenuated the proliferation and migration of AA-FLS. CK suppressed the secretion of proinflammatory cytokines TNF-α and downregulated the expression of TNFR2 on AA-FLS. In vitro CK also significantly suppressed proliferation, migration and secretion of AA-FLS mediated by TNF-α. Further studies showed that the effects of CK on AA-FLS were reversed by using glucocorticoid receptor (GR) antagonist (mifepristone). Our data suggest that CK exerts joint-protective effect by interfering with synoviocyte function mediated by TNF-α and TNFR2, and this effect may be mediated by GR. [ABSTRACT FROM AUTHOR]

In this study, a complete molecular characterization of tumor necrosis factor receptor 1 (TNFR1) which was identified from the constructed cDNA library of striped murrel Channa striatus ( Cs ) is reported. The Cs TNFR1 encoded a type I membrane receptor protein that contains 399 amino acids including three cysteine-rich domains (CRDs) at CRD1 41–46 , CRD2 79–118 and CRD3 120–159 in the extracellular region and a putative TNF receptor-associated factor (TRAF) site at 245–253 and a death domain between 297 and 388 in the cytoplasmic region which is essential for induction of apoptosis. The predicted molecular mass of Cs TNFR1 is 45 kDa and its corresponding theoretical isoelectric point (pI) is 6.3. Cs TNFR1 shared maximum identity with TNFR1 from olive flounder Paralichthys olivaceus (82%). Real-time PCR showed that Cs TNFR1 gene was expressed most abundantly ( P < 0.05) in the head kidney. Further, Cs TNFR1 mRNA transcription was studied after challenge with fungus Apanomyces invadans and bacteria Aeromonas hydrophila. The fungus injected murrels showed a highest expression at 48 h, whereas bacteria injected murrels showed at 24 h. The gene expression studies revealed that Cs TNFR1 may be involved in innate immune process of murrels against pathogenic infections. The over-expressed and purified recombinant Cs TNFR1 protein (r Cs TNFR1) was subjected to TNF-α inhibition assay to confirm their specificity and activity against TNF-α which confirmed that the r Cs TNFR1 inhibits the activity of TNF-α in a dose dependent manner where maximum inhibition (97%) was observed at 10,000 fold concentration of r Cs TNFR1. In addition, the direct cytotoxic effect of r Cs TNFR1 was analyzed against head kidney phagocyte. The results showed that the recombinant Cs TNFR1 protein does not exhibit any significant cytotoxicity against head kidney phagocyte cells even at higher concentration (8 μg/ml). Moreover, the recombinant protein was analyzed for respiratory burst activity in the presence of two different ROS inducers, opsonized zymosan (fungal cell wall component) and phorbol 12-myristate 13-acetate (PMA). The findings showed that the C. striatus head kidney phagocyte exposed to purified recombinant Cs TNFR1 protein alone do not produced any ROS. However, opsonized zymosan induced recombinant Cs TNFR1 protein significantly ( P < 0.05) enhanced the ROS production on concentration basis which is revealed that the ROS production depends on the concentration of the recombinant Cs TNFR1 protein. Overall, the study showed that the Cs TNFR1 plays an important role in the pathogen-induced inflammatory process of striped murrel. [ABSTRACT FROM AUTHOR]

Tumor Necrosis Factor (TNF), initially known for its tumor cytotoxicity, is a potent mediator of inflammation, as well as many normal physiological functions in homeostasis and health, and anti-microbial immunity. It also appears to have a central role in neurobiology, although this area of TNF biology is only recently emerging. Here, we review the basic biology of TNF and its normal effector functions, and discuss the advantages and disadvantages of therapeutic neutralization of TNF – now a commonplace practice in the treatment of a wide range of human inflammatory diseases. With over ten years of experience, and an emerging range of anti-TNF biologics now available, we also review their modes of action, which appear to be far more complex than had originally been anticipated. Finally, we highlight the current challenges for therapeutic intervention of TNF: (i) to discover and produce orally delivered small molecule TNF-inhibitors, (ii) to specifically target selected TNF producing cells or individual (diseased) tissue targets, and (iii) to pre-identify anti-TNF treatment responders. Although the future looks bright, the therapeutic modulation of TNF now moves into the era of personalized medicine with society's challenging expectations of durable treatment success and of achieving long-term disease remission. [ABSTRACT FROM AUTHOR]

Highlights: [•] Spared nerve injury (SNI) up-regulates TNFR1 and TNFR2 in the red nucleus (RN). [•] The up-regulation of TNFR2 in the RN of rats with SNI is earlier than that of TNFR1. [•] TNFR1 in the RN plays crucial role in the early and later stages of neuropathic pain. [•] TNFR2 in the RN plays an important role in the early stage of neuropathic pain. [ABSTRACT FROM AUTHOR]

Summary: Inflammation can be either beneficial or detrimental to the liver, depending on multiple factors. Mild (i.e., limited in intensity and destined to resolve) inflammatory responses have indeed been shown to exert consistent hepatoprotective effects, contributing to tissue repair and promoting the re-establishment of homeostasis. Conversely, excessive (i.e., disproportionate in intensity and permanent) inflammation may induce a massive loss of hepatocytes and hence exacerbate the severity of various hepatic conditions, including ischemia-reperfusion injury, systemic metabolic alterations (e.g., obesity, diabetes, non-alcoholic fatty liver disorders), alcoholic hepatitis, intoxication by xenobiotics and infection, de facto being associated with irreversible liver damage, fibrosis, and carcinogenesis. Both liver-resident cells (e.g., Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells) and cells that are recruited in response to injury (e.g., monocytes, macrophages, dendritic cells, natural killer cells) emit pro-inflammatory signals including – but not limited to – cytokines, chemokines, lipid messengers, and reactive oxygen species that contribute to the apoptotic or necrotic demise of hepatocytes. In turn, dying hepatocytes release damage-associated molecular patterns that-upon binding to evolutionary conserved pattern recognition receptors-activate cells of the innate immune system to further stimulate inflammatory responses, hence establishing a highly hepatotoxic feedforward cycle of inflammation and cell death. In this review, we discuss the cellular and molecular mechanisms that account for the most deleterious effect of hepatic inflammation at the cellular level, that is, the initiation of a massive cell death response among hepatocytes. [ABSTRACT FROM AUTHOR]

Abstract: Objective: There is evidence supporting that tumor necrosis factor receptor (TNFR)-signaling can induce production of beta-amyloid (Aβ) in the brain. Moreover, amyloid-induced toxicity has been shown to be dependent on TNFR-signaling. However, it is still unclear whether TNFRs are involved in the early stages of dementia. Methods: We analyzed soluble TNFR1 and TNFR2 levels in plasma and cerebrospinal fluid (CSF) at baseline in 137 patients with mild cognitive impairment (MCI) and 30 age-matched controls. The MCI patients were followed for 4–6 years with an incidence of Alzheimer''s disease (AD) or vascular dementia (VaD) of 15% per year. Results: The patients with MCI who subsequently developed these forms of dementias had higher levels of sTNFR1 and sTNFR2 in both CSF and plasma already at baseline when compared to age-matched controls (p <0.05). In the CSF of MCI subjects and controls the levels of both sTNFR1 and sTNFR2 correlated strongly with β-site APP-cleaving enzyme 1 (BACE1) activity (r s =0.53–0.68, p <0.01) and Aβ 40 levels (r s =0.59–0.71, p <0.001). Similarly, both sTNFRs were associated with Aβ 40 (r s =0.39–0.46, p <0.05) in plasma. Finally, the levels of both sTNFRs correlated with the axonal damage marker tau in the CSF of MCI subjects and controls (r s =0.57–0.83, p <0.001). Conclusion: TNFR-signaling might be involved in the early pathogenesis of AD and VaD, and could be associated with beta-amyloid metabolism. [Copyright &y& Elsevier]

Abstract: Objective: The tumor necrosis factor superfamily may exert cardioprotective or atherogenic effects, depending on the state of lesion progression. Tumor necrosis factor-α (TNF) induces macrophage ATP-binding cassette transporter A1 (ABCA1), a cardioprotective transmembrane protein that exports cellular cholesterol to apolipoprotein A-I. Here we examined the role of TNF receptors (TNFRs) in ABCA1 induction and tested the effects of lymphotoxin-α (LT), another TNF family member, on macrophage ABCA1 levels. Methods: Primary macrophages taken from mice deficient in TNF receptors were used to determine ABCA1 expression and cholesterol efflux activity in response to treatment with exogenous TNF or LT. Results: We studied TNFR2−/− and TNFR1−/−/R2−/− mice and found that both receptors are necessary for maximal induction of ABCA1 by TNF. Peritoneal macrophages from TNFR1−/−/R2−/− mice had no change in ABCA1 mRNA levels when treated with TNF while cells from TNFR2−/− mice had ABCA1 mRNA levels that were half that of wild-type (WT) cells. In contrast, incubating TNFR1−/−/R2−/− mice with LT increased ABCA1 by stabilizing the protein, which was not observed in WT mice and this was associated with downstream signaling through the LTβ receptor. Conclusion: TNF requires both of its receptors to maximally induce ABCA1. Despite previous studies suggesting that LT has proatherogenic properties, we found that LT increases ABCA1 protein in TNFR1−/−/R2−/− but not WT macrophages and may supplement TNF in enhancing ABCA1-dependent cholesterol export from early atherosclerotic lesions. [Copyright &y& Elsevier]

Abstract: Activation of transcription factor NF-κB can affect the expression of several hundred genes, many of which are involved in inflammation and immunity. The proper NF-κB transcriptional response is primarily regulated by post-translational modification of NF-κB signaling constituents. Herein, we review the accumulating evidence suggesting that alternative splicing of NF-κB signaling components is another means of controlling NF-κB signaling. Several alternative splicing events in both the tumor necrosis factor and Toll/interleukin-1 NF-κB signaling pathways can inhibit the NF-κB response, whereas others enhance NF-κB signaling. Alternative splicing of mRNAs encoding some NF-κB signaling components can be induced by prolonged exposure to an NF-κB-activating signal, such as lipopolysaccharide, suggesting a mechanism for negative feedback to dampen excessive NF-κB signaling. Moreover, some NF-κB alternative splicing events appear to be specific for certain diseases, and could serve as therapeutic targets or biomarkers. [Copyright &y& Elsevier]

Abstract: Src-suppressed C kinase substrate (SSeCKS), an in vivo and in vitro protein kinase C substrate, is a major lipopolysaccharide (LPS) response protein which markedly upregulated in several organs, including brain, lung, heart, kidney, etc., indicating a possible role of SSeCKS in inflammatory process. In the central nervous system (CNS), astrocytes play a pivotal role in immunity as immunocompetent cells by secreting cytokines and inflammatory mediators, there are two types of astrocytes. Type-1 astrocytes can secrete TNF-α when stimulated with lipopolysaccharide (LPS), while the responses of type-2 astrocytes during inflammation are unknown. So we examined the expression change of SSeCKS mRNA in type-2 astrocytes after exposure to TNF-α and LPS. Real-time PCR showed that TNF-α or LPS affected SSeCKS mRNA expression in a time- and dose-dependent manner. Now that LPS induces SSeCKS expression in type-2 astrocytes and type-1 astrocytes are well known to play a pivotal role in immunity, we compared SSeCKS mRNA expression in type-1 astrocytes with type-2 astrocytes after LPS stimulation. Real-time PCR showed that SSeCKS mRNA level was higher in normal untreated type-2 astrocytes than that in normal untreated type-1 astrocytes, increased significantly after 0.1–100 ng/ml LPS stimulation in type-2 astrocytes, but increased weakly after 10–100 ng/ml LPS stimulation in type-1 astrocytes. By using siRNA knockdown of SSeCKS expression, LPS-induced TNF-α synthesis and secretion in type-2 astrocytes were partly inhibited, which indicated that SSeCKS played a role in the TNF-α biosynthesis in type-2 astrocytes during the stimulation with LPS. RT-PCR analysis revealed that TNFR1 and TNFR2 were present in normal untreated type-2 astrocytes and that TNF-α, TNFR1 and TNFR2 increased in type-2 astrocytes after exposure to TNF-α or LPS. Immunocytochemistry showed that TNFR1 was expressed in the cytoplasm, nucleus and processes of normal untreated type-2 astrocytes and distributed mainly in the cytoplasm and processes after exposure to LPS. TNFR2 was mainly expressed in the nucleus of normal untreated type-2 astrocytes and distributed mainly in the processes of type-2 astrocytes after exposure to LPS. Both anti-TNFR1 and anti-TNFR2 antibodies suppressed SSeCKS mRNA expression induced by TNF-α or LPS. From these results, we conclude that TNF-α signaling via both TNFR1 and TNFR2 translocated from nucleus to cytoplasm or processes is sufficient to induce SSeCKS mRNA. In addition, we observed that not only exogenous TNF-α but also TNF-α produced by type-2 astrocytes affected SSeCKS mRNA production in type-2 astrocytes. These results suggest that an autocrine loop involving TNF-α contributes to the production of SSeCKS mRNA in response to inflammation. In addition, SSeCKS production was also drastically suppressed by U0126 (ERK inhibitor), SB203580 (p38 inhibitor), or SP600125 (SAPK/JNK inhibitor), which indicated that type-2 astrocytes which regulated SSeCKS expression after LPS stimulation were via ERK, SAPK/JNK, and P38MAP kinase signal pathway. [Copyright &y& Elsevier]

Abstract: We studied the effect of TNF-α stimulation on a cholangiocarcinoma cell line, CCKS1. CCKS1 expressed only one type TNF receptor, TNFR2. Treatment of CCKS1 with TNF-α substantially activated NFκB, MAPK and Akt signalings which in turn activated matrix metalloproteinase-9 (MMP-9) secretion and in vitro invasiveness of CCKS1. Pretreatment of cells with anti-TNFR2 neutralizing antibody inhibited the TNF-α-dependent signaling and MMP-9 secretion and subsequently blocked invasion in vitro. Moreover, an inhibitor for matrix metalloproteinase, Galardin, suppressed the invasion in a dose-dependent manner. Similarly, pharmacological inhibition of signaling clearly suppressed the TNF-α dependent MMP-9 secretion. These results strongly suggest that TNF-α-TNFR2 signaling plays an important role to convert the cholangiocarcinoma cells to be more aggressive one. [Copyright &y& Elsevier]

In this work, we studied the apoptotic pathway in murine fibrosarcoma cells L929 exposed to tumor necrosis factor α (TNF-α). DNA fragmentation, activation of caspases, cytochrome c release and poly (ADP-ribose) polymerase cleavage were demonstrated. We showed that the proapoptotic proteins Bid and Bax as well as caspase 8 are involved in the initiation of this apoptotic pathway triggered by TNF-α. Indeed, inhibition of caspase 8 could prevent TNF-α-induced DNA fragmentation. Furthermore, Bid and Bax translocation into mitochondria were already evidenced after 6 h. In contrast, permeability transition pore inhibitors did not prevent the DNA fragmentation induced by TNF-α. In addition, these events were not associated with changes in the mitochondrial membrane potential nor with the loss of ATP, which only occurred after 16 h. Taken together, these results underline the fact that TNF-α is able to induce caspase-dependent apoptosis in L929 in the absence of permeability transition pore opening. [Copyright &y& Elsevier]

We investigated the role of the CD134 (also named OX40) molecule in experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS). We examined the susceptibility of Cd134−/− mice to EAE, an autoimmune murine model that is dependent on infiltrating CD4+ T lymphocytes reactive to myelin proteins. EAE induced by myelin oligodendrocyte glycoprotein (MOG) injection in Cd134−/− mice showed less severe clinical signs of disease and markedly reduced inflammatory infiltrates within the central nervous system (CNS). Resistance was associated with a strong reduction of pathogenic IFNγ-producing T cells infiltrating the CNS of Cd134−/− mice. Furthermore, analysis of CNS tissue sections from EAE animals and MS patients revealed the presence of CD134+ cells that were localized in active lesions, mainly in perivascular infiltrates. The presence of CD134-expressing T cells in brain tissue of MS patients and EAE affected mice, together with the functional evidence provided by the significant decrease in disease score obtained in Cd134−/− mice, indicate that interfering with the CD134 molecule in T cells may be an appropriate target for therapeutic intervention in active MS. [Copyright &y& Elsevier]

Tumor necrosis factor receptor (TNFR) superfamily regulates diverse biologic functions, including cell proliferation, differentiation, and survival, in addition to providing costimulatory signals for programmed cell death or apoptosis. In this study, cDNA fragments for two distinct TNFR homologues were obtained from a Japanese flounder, Paralichthys olivaceus, cDNA library. Full-length cDNAs of TNFR-1 and TNFR-2 homologues were obtained by using these cDNA fragments as probes. The cDNA for the Japanese flounder TNFR-1 homologue predicts a peptide of 395 amino acids that is 35% identical to the extracellular region of mouse TNFR-1, whereas the cDNA of the Japanese flounder TNFR-2 homologue predicts a peptide of 483 amino acids that is 40% identical to the extracellular region of human TNFR-2. The cytoplasmic domain contains a sequence that has the consensus motif of the death domain of the Japanese flounder TNFR-1 homologue. In a healthy fish, the mRNAs of both TNFR homologues were predominantly expressed in leukocytes, kidney, gill, and spleen. Expression of the Japanese flounder TNFR-1 homologue was induced in peripheral blood lymphocytes (PBLs) after stimulation with LPS (500 μg/ml) for 1 h, and TNFR-2 homologue was strongly induced in PBLs after stimulation with Con A (50 μg/ml) and PMA (0.35 μg/ml) for 3 h. The different expression patterns of the two distinct TNFR homologues may be critical in determining whether binding with TNF-α or TNF-β have activating, proliferative, or apoptotic effects on target cells. [Copyright &y& Elsevier]

We examined the effects of exercise training (treadmill running over 9 weeks) on the ability of isolated adipocytes to secrete tumor necrosis factor-α (TNF–α) and type 1 soluble TNF receptor (sTNFR1) in vitro in Wistar rats. We also examined the effects of exercise training on the expression of membrane bound forms of type 1 TNF receptor (mTNFR1) in adipocyte crude membranes of the same rat subjects. Exercise training significantly increased the secretions of TNF–α from isolated adipocytes. Treatment with a cyclooxygenase inhibitor, either indomethacin (100 μM) or eicosatetraynoic acid (100 μM), significantly blocked the release of TNF–α from adipocytes in both exercise-trained rat group and sedentary control rat group, suggesting that some cyclooxygenase metabolite(s) acts as a ligand in TNF–α synthesis. Decreased amounts of TNF–α were found to be significantly greater in both exercise-trained rat group than in sedentary control rat group after incubation with inhibitors. Thus, the inhibitory effect of both indomethacin and eicosatetraynoic acid was significantly greater in adipocytes from exercise-trained rats. Both plasma sTNFR1 levels and adipocytes-derived sTNFR1 were found to be significantly less in the exercise-trained rat group. Western blot analysis revealed that exercise training remarkably increased the expressions of mTNFR1 in adipocyte crude membrane. Thus, exercise training enhanced the ability of isolated adipocytes to secrete TNF–α with reduced secretion of sTNFR1, and provoked the greater expressions of mTNFR1 in adipocyte crude membrane. These alterations may induce enhanced the autocrine effects of TNF–α within adipocytes in exercise-trained rats. [Copyright &y& Elsevier]

Tumor-associated tertiary lymphoid structures (TA-TLS) are associated with enhanced patient survival and responsiveness to cancer therapies, but the mechanisms underlying their development are unknown. We show here that TA-TLS development in murine melanoma is orchestrated by cancer-associated fibroblasts (CAF) with characteristics of lymphoid tissue organizer cells that are induced by tumor necrosis factor receptor signaling. CAF organization into reticular networks is mediated by CD8 T cells, while CAF accumulation and TA-TLS expansion depend on CXCL13-mediated recruitment of B cells expressing lymphotoxin-α 1 β 2. Some of these elements are also overrepresented in human TA-TLS. Additionally, we demonstrate that immunotherapy induces more and larger TA-TLS that are more often organized with discrete T and B cell zones, and that TA-TLS presence, number, and size are correlated with reduced tumor size and overall response to checkpoint immunotherapy. This work provides a platform for manipulating TA-TLS development as a cancer immunotherapy strategy. [Display omitted] • Cancer-associated fibroblasts orchestrate tertiary lymphoid structures in tumors • CD8 T cells and B cells drive tertiary lymphoid structure development via fibroblasts • Tertiary lymphoid structure development is mediated by TNF and lymphotoxin receptors • Checkpoint blockade alters tertiary lymphoid structures together with tumor control Rodriguez et al. describe the cellular and molecular mechanisms driving development of tumor-associated tertiary lymphoid structures and the importance of these structures as mediators of anti-tumor immunity and response to checkpoint immunotherapy. [ABSTRACT FROM AUTHOR]

• higher CSF levels of TNF-α related inflammatory proteins in the MCI and AD patients with positive tau pathology. • TNF receptors were associated with t-tau and p-tau, other than Aβ 1-42 , in HC, MCI and AD subjects. • TNF receptors are potential early predictors for the MCI-to-AD conversion. Tumor necrosis factor-a (TNF-α) signaling pathway plays a significant role in Alzheimer's disease (AD). This study aimed to explore the relationship between TNF-α related inflammatory proteins and pathological markers of AD, and examine their possibility as a predictor of the conversion of mild cognitive impairment (MCI) to AD. This study included both cross-sectional and longitudinal designs. The levels of TNF-α related inflammatory proteins, Aβ 1-42 , total-tau(t-tau), phosphorylated tau (p-tau) from cerebrospinal fluid (CSF) were analyzed in healthy controls (HC, n = 90), MCI (n = 116), and AD participants (n = 75) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Kaplan-Meier analyses were used to evaluate the predictive value of the examined putative AD markers after follow-up visits. In the cross-sectional cohort, we observed higher CSF levels of TNF-α related inflammatory proteins in the MCI and AD patients with positive tau pathology. TNF receptors (TNFR) were more closely associated with t-tau and p-tau than Aβ 1-42 , in HC, MCI and AD subjects. In the longitudinal cohort with a mean follow-up of 30.2 months, MCI patients with high levels of CSF TNFR1 (p = 0.001) and low levels of TNFR2 (p < 0.001) were more likely to develop into AD. TNFR-signaling might be involved in the early pathogenesis of AD and TNF receptors may serve as potential predictive biomarkers for MCI. [ABSTRACT FROM AUTHOR]