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Intravenous infusion of relatively higher doses of angiotensin II (AngII) elicits natriuresis as opposed to its usual anti‐natruretic response. As AngII can induce tumor necrosis factor‐α (TNFα) production which elicits natriuresis via its action on TNFα receptor type 1 (TNFR1), we hypothesize that the concomitant release of TNFα contributes to the natriuretic response to AngII. Responses to AngII infusion (1 ng min−1 g−1 for 75 min, iv) were evaluated in anesthetized knockout (KO) mice lacking TNFR1 (n = 6) and TNFR2 (TNFα receptor type 2; n = 6) and compared these responses with those in wild type (WT; n = 6) mice. Arterial pressure (AP) was recorded from a cannula placed in the carotid artery. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by PAH and inulin clearances, respectively. Urine was collected from a catheter placed in the bladder. AngII caused similar increases (p < 0.05 vs basal values) in AP (WT, 37 ± 5%; TNFR1KO, 35 ± 4%; TNFR2KO, 30 ± 4%) and decreases (p < 0.05) in RBF (WT, −39 ± 5%; TNFR1KO, −28 ± 6%; TNFR2KO, −31 ± 4%) without significant changes in GFR (WT, −17 ± 7%; TNFR1KO, −18 ± 7%; TNFR2KO, −12 ± 7%). However, despite similar changes in AP and renal hemodynamics, AngII induced increases (p < 0.05) in urinary sodium excretion in WT (3916 ± 942%) were less in the KO strains, more or less in TNFR1KO (473 ± 170%) than in TNFR2KO (1176 ± 168%). These data indicate that TNF‐α receptors, particularly TNFR1 are involved in the natriuretic response that occur during acute infusion of AngII and thus, plays a protective role in preventing excessive salt retention at clinical conditions associated with elevated AngII level. Short summary of the study: The present study examined the role of concomitant TNF‐α formation in regulating renal responses to angiotensin II (AngII) by evaluating its effects in mice lacking TNF receptor type 1 (TNFR1KO) and type 2 (TNFR2KO) and compared to that in WT mice. The results showed that TNFR1 activation is involved in the natriuresis induced by AngII and suggest a protective role of TNFR1 in preventing excessive salt retention during elevated AngII level.

In hypertension induced by angiotensin II (AngII) administration with high salt (HS) intake, intrarenal angiotensinogen (AGT) and tumor necrosis factor‐alpha (TNF‐α) levels increase. However, TNF‐α has been shown to suppress AGT formation in cultured renal proximal tubular cells. We examined the hypothesis that elevated AngII levels during HS intake reduces TNF‐α receptor type 1 (TNFR1) activity in the kidneys, thus facilitating increased intrarenal AGT formation. The responses to HS diet (4% NaCl) with chronic infusion of AngII (25 ng/min) via implanted minipump for 4 weeks were assessed in wild‐type (WT) and knockout (KO) mice lacking TNFR1 or TNFR2 receptors. Blood pressure was measured by tail‐cuff plethysmography, and 24‐h urine samples were collected using metabolic cages prior to start (0 day) and at the end of 2nd and 4th week periods. The urinary excretion rate of AGT (uAGT; marker for intrarenal AGT) was measured using ELISA. HS +AngII treatment for 4 weeks increased mean arterial pressure (MAP) in all strains of mice. However, the increase in MAP in TNFR1KO (77 ± 2 to 115 ± 3 mmHg; n = 7) was significantly greater (p < 0.01) than in WT (76 ± 1 to 102 ± 2 mmHg; n = 7) or in TNFR2KO (78 ± 2 to 99 ± 5 mmHg; n = 6). The increase in uAGT at 4th week was also greater (p < 0.05) in TNFR1KO mice (6 ± 2 to 167 ± 75 ng/24 h) than that in WT (6 ± 3 to 46 ± 16 ng/24 h) or in TNFR2KO mice (8 ± 7 to 65 ± 44 ng/24 h). The results indicate that TNFR1 exerts a protective role by mitigating intrarenal AGT formation induced by elevated AngII and HS intake. We examined the hypothesis that elevated AngII levels during HS intake reduce TNF‐α receptor type 1 (TNFR1) activity in the kidneys, thus facilitating increased intrarenal AGT formation. The responses to HS diet (4% NaCl) with chronic infusion of AngII (25 ng/min) via implanted minipump for 4 weeks were assessed in wild‐type (WT) and knockout (KO) mice lacking TNFR1 and TNFR2 receptors. HS +AngII treatment for 4 weeks increased mean blood pressure (MBP) in all strains of mice. However, the increase in MBP in TNFR1KO was greater than that in WT or in TNFR2KO. The increase in urinary angiotensinogen excretion (UAGT) at the 4th week was also greater in TNFR1KO mice than that in WT or in TNFR2KO mice. The results indicate that TNFR1 activity exerts a protective role by mitigating intrarenal AGT formation induced by elevated AngII and HS intake.

Tumor necrosis factor (TNF)-α is a pleiotropic cytokine implicated in the etiology of several autoimmune diseases, including rheumatoid arthritis (RA). TNF-α regulates diverse effector functions through the activation of TNF-α receptor (TNFR)1 and TNFR2. Although the detrimental role of this cytokine has been addressed in distinct disease settings, the effects of TNF-α on cytokine production by isolated CD4+ T helper type 1 (Th1) and Th17 cells, two T cell subpopulations that contribute to the pathogenesis of RA, have not been completely elucidated. Here, we show that TNF-α promotes a reduction and expansion in the frequency of both T cell subsets producing IFN-γ and IL-17, respectively. Selective blockade of TNFR1 or TNFR2 on Th1 and Th17 cells revealed that TNFR2 mediates the decrease in IFN-γ production, while signaling through both receptors augments IL-17 production. We also demonstrate that Th1, but not Th17 cells from RA patients present lower levels of TNFR1 compared to healthy controls, whereas TNFR2 expression on both T cell types is similar between patients and controls. Since TNF-α receptors levels in RA patients are not significantly changed by the therapeutic blockade of TNF-α, we propose that targeting TNFR2 may represent an alternative strategy to normalize the levels of key cytokines that contribute to RA pathogenesis.

Pregnancy is a complex biological process. The establishment and maintenance of foetal–maternal interface are pivotal events. Decidual immune cells and inflammatory cytokines play indispensable roles in the foetal–maternal interface. The disfunction of decidual immune cells leads to adverse pregnancy outcome. Tumour necrosis factor (TNF)-α, a common inflammatory cytokine, has critical roles in different stages of normal pregnancy process. However, the relationship between the disorder of TNF-α and adverse pregnancy outcomes, including preeclampsia (PE), intrauterine growth restriction (IUGR), spontaneous abortion (SA), preterm birth and so on, is still indefinite. In this review, we thoroughly reviewed the effect of TNF-α disorder on pathological conditions. Moreover, we summarized the reports about the adverse pregnancy outcomes (PE, IUGR, SA and preterm birth) of using anti-TNF-α drugs (infliximab, etanercept and adalimumab, certolizumab and golimumab) currently in the clinical studies. Overall, IUGR, SA and preterm birth are the most common adverse pregnancy outcomes of anti-TNF-α drugs. Our review may provide insight for the immunological treatment of pregnancy-related complication, and help practitioners make informed decisions based on the current evidences.

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine associated with TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2), which play important roles in several inflammatory diseases. There is a growing interest in developing alternative molecules that can be used as TNF blockers. In this study, we focused on TNF-α-, TNFR1-, and TNFR2-mimicking peptides to inhibit TNF-α receptor binding in various ways. Six peptides (OB1, OB2, OB5, OB6, OB7, and OB8) were developed to bind TNFR1, TNFR2, and TNF-α. OB1 and OB2 bound to TNF-α with lower Kd values of 300 and 46.7 nM, respectively, compared to previously published sequences. These synthetic peptides directly and indirectly inhibited TNF-α in vitro without cytotoxicity to L929 cells, and OB1 significantly inhibited apoptosis in the presence of hTNF-α. Peptides developed in this study may prove to be useful for therapeutic inhibition of TNF-α.

Psoriasis (PsO) and Psoriatic arthritis (PsA) are TNF-alpha-dependent immune-mediated inflammatory diseases where dendritic cells (DC) play a critical role in disease pathogenesis. Although TNF-alpha receptor 2 (TNFR2) has been implicated in the pathology of psoriatic diseases, its specific role in DC mediated responses remains unclear. To investigate the role of TNFR2 in DC in psoriatic disease, we utilized the mannan-oligosaccharide (MOS) model of PsA on mice with either TNFR2 intact or with DC-specific TNFR2 knockout (DC-TNFR2KO). We evaluated disease severity by assessing skin scaling, joint inflammation, serum cytokine profiles, and changes in the conventional type 1 dendritic cell (cDC1) population. A significant reduction in PsA-like skin scaling and joint inflammation was observed in DC-TNFR2KO mice. In control mice, MOS stimulated a robust increase in the cDC1 population, a response that was notably suppressed in the absence of DC-TNFR2. Furthermore, serum levels of key pro-inflammatory cytokines such as interleukin-12 (IL-12), TNF-alpha, IL-23 and IL-17 A were significantly diminished in DC-TNFR2KO mice following MOS exposure. Our findings provide compelling evidence that TNFR2 signaling in DC is instrumental in promoting PsA-like inflammation. These results highlight the potential of targeting the DC-TNFR2-pathways as a novel therapeutic strategy for PsA and related immune-mediated inflammatory diseases.

Background Epidemiological emerging evidence shows that human exposure to some nanosized materials present in the environment would contribute to the onset and/or progression of Alzheimer’s disease (AD). The cellular and molecular mechanisms whereby nanoparticles would exert some adverse effects towards neurons and take part in AD pathology are nevertheless unknown. Results Here, we provide the prime evidence that titanium dioxide (TiO 2 ) and carbon black (CB) nanoparticles (NPs) bind the cellular form of the prion protein (PrP C ), a plasma membrane protein well known for its implication in prion diseases and prion-like diseases, such as AD. The interaction between TiO 2 - or CB-NPs and PrP C at the surface of neuronal cells grown in culture corrupts PrP C signaling function. This triggers PrP C -dependent activation of NADPH oxidase and subsequent production of reactive oxygen species (ROS) that alters redox equilibrium. Through PrP C interaction, NPs also promote the activation of 3-phosphoinositide-dependent kinase 1 (PDK1), which in turn provokes the internalization of the neuroprotective TACE α-secretase. This diverts TACE cleavage activity away from (i) TNFα receptors (TNFR), whose accumulation at the plasma membrane augments the vulnerability of NP-exposed neuronal cells to TNFα -associated inflammation, and (ii) the amyloid precursor protein APP, leading to overproduction of neurotoxic amyloid Aβ40/42 peptides. The silencing of PrP C or the pharmacological inhibition of PDK1 protects neuronal cells from TiO 2 - and CB-NPs effects regarding ROS production, TNFα hypersensitivity, and Aβ rise. Finally, we show that dysregulation of the PrP C -PDK1-TACE pathway likely occurs in the brain of mice injected with TiO 2 -NPs by the intra-cerebro-ventricular route as we monitor a rise of TNFR at the cell surface of several groups of neurons located in distinct brain areas. Conclusion Our in vitro and in vivo study thus posits for the first time normal cellular prion protein PrP C as being a neuronal receptor of TiO 2 - and CB-NPs and identifies PrP C -coupled signaling pathways by which those nanoparticles alter redox equilibrium, augment the intrinsic sensitivity of neurons to neuroinflammation, and provoke a rise of Aβ peptides. By identifying signaling cascades dysregulated by TiO 2 - and CB-NPs in neurons, our data shed light on how human exposure to some NPs might be related to AD.

TNFα is the main proinflammatory cytokine implicated in the pathogenesis of neurodegenerative disorders, but it also modulates physiological functions in both the developing and adult brain. In this study, we investigated a potential direct role of TNFα in determining phenotypic changes of a recently established cellular model of human basal forebrain cholinergic neuroblasts isolated from the nucleus basalis of Meynert (hfNBMs). Exposing hfNBMs to TNFα reduced the expression of immature markers, such as nestin and β-tubulin III, and inhibited primary cilium formation. On the contrary, TNFα increased the expression of TNFα receptor TNFR2 and the mature neuron marker MAP2, also promoting neurite elongation. Moreover, TNFα affected nerve growth factor receptor expression. We also found that TNFα induced the expression of DNA-methylation enzymes and, accordingly, downregulated genes involved in neuronal development through epigenetic mechanisms, as demonstrated by methylome analysis. In summary, TNFα showed a dual role on hfNBMs phenotypic plasticity, exerting a negative influence on neurogenesis despite a positive effect on differentiation, through mechanisms that remain to be elucidated. Our results help to clarify the complexity of TNFα effects in human neurons and suggest that manipulation of TNFα signaling could provide a potential therapeutic approach against neurodegenerative disorders.

Bovine leukemia virus (BLV) main host cells are B lymphocytes. Infected animals can be classified into high or low proviral load (HPL or LPL respectively), regarding the number of proviral copies infected lymphocytes they carry. After infection, there is an overexpression of several cytokines, particularly TNF-α, which has a delicate regulation mediated by receptors TNFRI and TNFRII; the first one involved with apoptosis, while the other stimulates cell proliferation. The study aimed to quantify TNF-α and its receptors mRNA expression, and in which extent in vitro proliferation was affected, in peripheral blood mononuclear cells (PBMC) from BLV-infected animals with different proviral loads, after the addition or not of synthetic TNF-α (rTNF-α) for 48 h. PBMC from BLV-infected animals showed spontaneous proliferation after 48 h in culture but did not show changes in proliferation rates after 48 h incubation in the presence of the rTNF-α. TNF-α mRNA expression after 48 h culture without exogenous stimulation was significantly lower, regardless of the proviral load of the donor, compared to non-infected animals. In the LPL animals, the expression of TNF-α mRNA was significantly lower with respect to the control group while the expression of TNFRI mRNA was significantly increased. The HPL animals showed a significant decrease in the expression of TNF-α and TNFRII mRNA respect to the control group. After 48 h incubation with rTNF-α, PBMC from infected animals had different responses: TNF-α and TNFRI mRNA expression was reduced in PBMC from the LPL group compared to the BLV negative group, but no differences were observed in PBMC from the HPL group. TNFRII mRNA expression showed no differences between HPL, LPL, and BLV negative groups, though HPL animals expressed 10.35 times more TNFRI mRNA than LPL. These results support the hypothesis that LPL animals, when faced with viral reactivation, present a pro-apoptotic and anti-proliferative state. However, complementary studies are needed to explain the influence of TNFRII on the development of the HLP profile. On the other hand, exogenous stimulation studies reinforce the hypothesis that BLV infection compromises the immune response of the animals.

Objective To determine the involvement of TNF-α and glycine receptors in the inhibition of pro-inflammatory adipokines in 3T3-L1 cells. Methods RT-PCR evidenced glycine receptors in 3T3-L1 adipocytes. 3T3-L1 cells were transfected with siRNA for the glycine (Glrb) and TNF1a (Tnfrsf1a) receptors and confirmed by confocal microscopy. Transfected cells were treated with glycine (10 mM). The expressions of TNF-α and IL-6 mRNA were measured by qRT-PCR, while concentrations were quantified by ELISA. Results Glycine decreased the expression and concentration of TNF-α and IL-6; this effect did not occur in the absence of TNF-α receptor due to siRNA. In contrast, glycine produced only slight changes in the expression of TNF-α and IL-6 in the absence of the glycine receptor due to siRNA. A docking analysis confirmed the possibility of binding glycine to the TNF-α1a receptor. Conclusion These findings support the idea that glycine could partially inhibit the binding of TNF-α to its receptor and provide clues about the mechanisms by which glycine inhibits the secretion of pro-inflammatory adipokines in adipocytes through the TNF-α receptor.