Tumor Necrosis Factor-alpha Receptor Research Articles

FRI-217 - Deletion of tumor necrosis factor alpha receptor 1 leads to an increased Th17 cell response in the chronically inflamed liver

FRI-217 - Deletion of tumor necrosis factor alpha receptor 1 leads to an increased Th17 cell response in the chronically inflamed liver

Effects of Vaccination Against the H1N1 Virus on BDNF and TNF-α Plasma Levels in Pregnant Women.

Vaccination is a widespread strategy to protect women and their children during fetal development. However, there is a lack of knowledge about potential effects of H1N1 vaccination on concentration of cytokines that are important to mother's central nervous system functions and fetal neurodevelopment. The main purpose of the present study was to evaluate such interaction. The specific goals were to study the effects of vaccination against the H1N1 virus on plasma levels of the Brain Derived Neurotrophic Factor(BDNF), Tumor Necrosis Factor-α (TNF-α) and TNF-α Receptors 1 and 2 (sTNFR1; sTNFR2), in different periods of gestation. Data were obtained during the period of 6 months in 2010, from a sample of 94 pregnant women who were using the health care service of Conceição do Mato Dentro, a rural area in the state of Minas Gerais, Brazil. Seventeen women were in the first trimester of pregnancy, forty were in the second trimester and 37 were in the third trimester. Each of these groups was divided into two subgroups as follows: immunized against the H1N1 virus (I) and non-immunized (NI). Plasma concentrations of BDNF, TNF-α, sTNFR1 and sTNFR2 were measured using the sandwich ELISA. There was no difference in cytokine or neurotrophic factor levels evaluated between groups I and NI in any trimesters. These results show that the recommendation of vaccination against the H1N1 virus for all pregnant women as a public health measure could be considered safe, regarding aspects related to the role played by neurotrophin and cytokine, such as those of CNS development and immunological functions.

Inflammation and Trajectory of Renal Function in Community-Dwelling Older Adults.

To examine the hypothesis that the inflammatory state of aging is a risk factor for accelerated renal function (RF) decline using inflammatory biomarkers and RF measures collected over 9 years of follow-up in relatively healthy individuals enrolled in the Invecchiare in Chianti study. Longitudinal. Community. Individuals aged 60 and older with baseline estimated glomerular filtration rate (eGFR) of 60 mL/min per 1.73 m2 and greater and no diabetes mellitus (DM) (N = 687). eGFR, as a proxy for RF, was determined using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at baseline and 3-, 6-, and 9-year follow-up. Incident chronic kidney disease (CKD) was defined as new-onset eGFR less than 60 mL/min per 1.73 m2 at each follow-up. Predictors included baseline and time-dependent inflammatory biomarkers: soluble tumor necrosis factor alpha receptors (sTNFα-R1 and -R2), interleukin (IL)-6, IL-18, IL-1β, IL-1 receptor antagonist, and high-sensitivity C-reactive protein. Higher baseline sTNFα-R1 was significantly associated with lower eGFR over 9 years, independent of DM or blood pressure (baseline: β^ = -0.39, P = .001; 3-year: β^ = -0.26, P = .001; 6-year: β^ = -0.36, P = .001; 9-year: β^ = -0.47, P = .001). The rate of TNFα-R1 change was significantly associated with rate of eGFR change (β^ = -0.18, P = .001). Baseline sTNFα-R1 predicted incident CKD (per 1-standard deviation increment: 3-year: relative risk (RR) = 1.3, 95% confidence interval (CI) = 1.1-1.5; 6-year: RR = 1.5, 95% CI = 1.1-2.2; 9-year RR = 1.6, 95% CI = 1.1-2.2). Similar results were found for sTNFα-R2. Baseline TNFα-R levels and their rates of change were significantly associated with RF decline and incident CKD in older adults independent of DM or blood pressure.

Low-grade Inflammatory Marker Profile May Help to Differentiate Patients With LADA, Classic Adult-Onset Type 1 Diabetes, and Type 2 Diabetes.

To test whether differences in serum concentrations of adiposity-related low-grade inflammatory mediators could help to differentiate patients with latent autoimmune diabetes in adults (LADA), classic adult-onset type 1 diabetes, and type 2 diabetes. This cross-sectional study involved 75 patients with LADA, 67 with classic adult-onset type 1 diabetes, and 390 with type 2 diabetes. Serum concentrations of adiponectin, soluble tumor necrosis factor-α receptor 2 (sTNFRII), interleukin-6, hs-CRP, and total leukocyte number were measured. To evaluate the differences of these markers among diabetes types, we performed logistic regression models and evaluated area under the receiver-operating characteristic curve (AUCROC) values. The profile of innate immunity-related inflammatory markers correlated with metabolic syndrome components. LADA versus classic adult-onset type 1 diabetes was independently related to sTNFRII (odds ratio [OR] 1.9 [95% CI 1.01-3.97]; P = 0.047) and hs-CRP levels (OR 0.78 [95% CI 0.62-0.96]; P = 0.019), and a higher number of total leukocytes lowered the risk of LADA compared with type 2 diabetes (OR 0.98 [95% CI 0.97-0.99]; P = 0.036). The logistic regression model including explanatory biomarkers explained 35% of the variation for LADA versus classic adult-onset type 1 diabetes (AUCROC 0.83 [95% CI 0.74-0.92]; P < 0.001) and 15% of the variation for LADA versus type 2 diabetes (AUCROC 0.73 [95% CI 0.70-0.80]; P < 0.001). Inflammatory, adiposity, and immune-related markers could help to differentiate a LADA diagnosis from that of classic adult-onset type 1 diabetes, and also LADA from that of type 2 diabetes, along with islet autoantibody positivity.

Analysis of biomarker serum levels in IVIG and infliximab refractory Kawasaki disease patients.

Infliximab (IFX) is effective for treatment of refractory Kawasaki disease (KD). However, the precise mechanisms and biomarkers for IFX efficacy are unknown. We tried to evaluate the effect and response to IFX therapy by measuring serum cytokine levels. Twenty-nine children with KD who had been resistant to two courses of high-dose intravenous immunoglobulin were enrolled and treated with IFX. Plasma samples were analyzed for cytokines before and after IFX administration. Serum levels of interleukin-6, granulocyte colony-stimulating factor (G-CSF), interferon-gamma-induced monokine, interferon-gamma inducible protein 10 (IP-10), monocyte chemotactic protein 1, and soluble tumor necrosis factor-alpha receptor (sTNFR) 1 and 2 were significantly elevated before IFX treatment, but promptly decreased after the administration. The pre-treatment G-CSF and sTNFR1 levels in non-responders to IFX were significantly higher than in responders, who were defined as patients who defervesce (< 37.5°C). After IFX administration, elevated cytokines declined to normal ranges in responders, but in non-responsive group, G-CSF and sTNFR1 remained elevated without failing to normal levels. IFX treatment significantly reduced the levels of serum cytokines, chemokines, and sTNFRs in refractory KD. G-CSF and sTNFR1 may be indicators predictive of poor response to IFX.

Potential role of soluble TNF-α receptors in diagnosis of idiopathic membranous nephropathy

Soluble tumor necrosis factor alpha (TNF-α) receptors contain two receptors: soluble tumor necrosis factor receptor (sTNFR) 1 and 2, and the aim of our study was to discover their concentration and diagnostic value for idiopathic membranous nephropathy (IMN). In total, 58 patients with IMN, 51 patients with chronic kidney disease (CKD), and 30 healthy volunteers were enrolled in this study. Levels of serum sTNFR1 and sTNFR2 were determined by enzyme-linked immunosorbent assay (ELISA). Serum cystatin C (CysC), urea, creatinine (CREA), uric acid (UA), total protein (TP), albumin (ALB), and 24-h urinary protein (proteinuria, PRO) were examined by automatic biochemical analyzer. Levels of sTNFR1 and sTNFR2 were significantly higher in IMN group than CKD and control group ( P &lt; 0.05). In IMN group, there were significant correlation between sTNFR1 and sTNFR2 ( P &lt; 0.01). Both sTNFR1 and sTNFR2 were positively related to serum urea, CREA, CysC, UA, 24-h PRO ( P &lt; 0.05) and negatively related to ALB ( P &lt; 0.01). Receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) of sTNFR1 and sTNFR2 were 0.997 and 0.993, respectively, when control was healthy volunteers. When sTNFR1 cut-off was 959.15 pg/mL, the sensitivity and specificity were 96.6% and 100%, respectively. When sTNFR2 cut-off was 2449.43 pg/mL, the sensitivity and specificity were 93.1% and 100%, respectively. While the control was CKD group, AUC of sTNFR1 and sTNFR2 were 0.647 and 0.626, respectively. When sTNFR1 cut-off was 3356.57 pg/mL, the sensitivity and specificity were 72.4% and 60.8%, respectively. When sTNFR2 cut-off was 6497.34 pg/mL, the sensitivity and specificity were 72.4% and 58.8%, respectively. This is the first study to show that both levels of sTNFR1 and sTNFR2 increased and correlated with serum urea, CREA, CysC, UA, ALB, 24-h PRO and could be usable for IMN diagnosis and differential diagnosis between IMN and CKD.

Leucine alters immunoglobulin a secretion and inflammatory cytokine expression induced by lipopolysaccharide via the nuclear factor-κB pathway in intestine of chicken embryos

The mammalian target of rapamycin (mTOR) has been shown to be involved in lipopolysaccharide (LPS)-induced immune responses in many mammal cells. Here, we suggest that the mTOR pathway is involved in the intestinal inflammatory responses evoked by LPS treatment in chicken embryos. The intestinal tissue from Specific pathogen free chick embryos was cultured in the presence of LPS for 2 h. Secretory immunoglobulin A (sIgA) concentrations, messenger RNA (mRNA) expression of cytokines, and protein levels of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), mTOR and p70 ribosomal S6 kinase (p70S6K) were determined. The results showed that LPS treatment increased sIgA concentrations in a dose-dependent manner. The mRNA levels of interleukine (IL)-6, IL-8, IL-10, tumor necrosis factor-α and Toll-like receptor (TLR) 4 were upregulated by LPS treatment (P<0.05). Lipopolysaccharide increased the phosphorylation of Jun N-terminal kinase (JNK), p38 MAPK and NF-κB (P<0.05) while decreasing the phosphorylation level of mTOR (P<0.05). Supplementation of leucine at doses of 10, 20 and 40 mM dose-dependently decreased sIgA production. Leucine supplementation at 40 mM restored the phosphorylation level of mTOR and p70S6K while suppressing the phosphorylation levels of NF-κB (P<0.05) and partially down-regulating the phosphorylation of p38 MAPK and JNK. The transcription of IL-6 was significantly decreased by leucine supplementation. These results suggested that leucine could alleviate LPS-induced inflammatory responses by down-regulating NF-κB signaling pathway and evoking mTOR/p70S6K signaling pathway, which may involve in the regulation of the intestinal immune system in chicken embryos.

Tumor necrosis factor receptor in Egyptian patients with bipolar disorder during mania: a case–controlled study

Background The role of inflammation has received increasing attention as a potential pathophysiological mechanism in bipolar disorder (BD). Objective To compare the level of soluble tumor necrosis factor-α receptor 1 (sTNFR1) in manic state of BD with healthy controls and investigate the relation between its level and the severity of BD. Patients and methods Serum levels of sTNFR1 were measured with enzyme-linked immunosorbent assay techniques in 44 patients with BD-I during the manic episode and 88 healthy controls recruited from Kasr Al Ainy Hospital, Cairo University. The severity of the manic symptoms was assessed using Young Mania Rating Scale. Results The level of sTNFR1 was higher in patients with BD-I, with the most recent episode manic, than in healthy control. Patients with BD-I, with the most recent episode manic, with psychotic features had higher levels of sTNFR1 than those without psychotic features. sTNFR1 level correlated with Young Mania Rating Scale scores. Conclusion High level of sTNFR1 may be considered as state marker in manic episodes in patients with BD-I. The more severe the disease, the higher the level of sTNFR1.

Perilla extract improves frequent urination in spontaneously hypertensive rats with enhancement of the urothelial presence and anti-inflammatory effects.

To investigate the effects of perilla extract on urinary symptoms in spontaneously hypertensive rats as a model of spontaneous overactive bladder. Spontaneously hypertensive rats were randomly divided into two groups and fed either a control diet or a perilla extract-containing diet. Cystometry, gene expression and histological analyses were carried out to evaluate the effects of perilla extract after 2-week feeding of either the control or the perilla extract diet. The expression of inflammation-related genes in the human urothelial cell line HT-1376 and the normal human bladder epithelial cell was measured after the treatment with perillaldehyde, the main component of perilla extract, or perillic acid, the final metabolite of perillaldehyde. A significant 27% increase in the micturition interval and decreased expression of nerve growth factor, tumor necrosis factor-α, interleukin-1β and transient receptor potential V1 were observed in the perilla group compared with the control group. The level of uroplakin 3A was 40% higher in the perilla group than in the control group. The urothelium in the control group was thin or defective, but it was almost completely intact in the perilla group. Perillaldehyde and perillic acid suppressed the induction of nerve growth factor and tumor necrosis factor-α by interleukin-1β in HT-1376 and normal human bladder epithelial cells. The present findings suggest that perilla extract improves frequent urination, and this improvement seems to be mediated, at least in part, by enhancement of the urothelial presence and by the anti-inflammatory effects of perilla.

Anti-hyperglycemic and anti-hyperlipidaemic effect of Arjunarishta in high-fat fed animals

BackgroundArjunarishta (AA), a formulation used as cardiotonic is a hydroalcoholic formulation of Terminalia arjuna (Roxb.) Wight and Arn. (TA) belonging to family Combretaceae. ObjectiveTo evaluate the anti-hyperglycemic and anti-hyperlipidemic effect of Arjunarishta on high-fat diet fed animals. Materials and methodsHigh-fat diet fed (HFD) Wistar rats were randomly divided into three groups and treated with phytochemically standardized Arjunarishta (1.8 ml/kg), and hydroalcoholic extract of T. arjuna (TAHA) (250 mg/kg) and rosuvastatin (10 mg/kg), for 3 months. Intraperitoneal glucose tolerance test, blood biochemistry, liver triglyceride and systolic blood pressure were performed in all the groups. Effect of these drugs on the expression of tumor necrosis factor-α (TNF-α) and insulin receptor substrate-1 (IRS-1) and peroxisome proliferators activated receptor γ coactivator 1-α (PGC-1α) were studied in liver tissue using Quantitative Real-time PCR. ResultsHFD increased fasting blood glucose, liver triglyceride, systolic blood pressure and gene expression of TNF-α, IRS-1 and PGC-1α. Treatment of AA and TAHA significantly reduced fasting blood glucose, systolic blood pressure, total cholesterol and triglyceride levels. These treatments significantly decreased gene expression of TNF-α (2.4, 2.2 and 2.6 fold change); increased IRS-1 (2.8, 2.9 and 2.8 fold change) and PGC-1α (2.9, 3.7 and 3.3 fold change) as compared to untreated HFD. ConclusionAnti-hyperglycemic, anti-hyperlipidemic effect of Arjunarishta may be mediated by decreased TNF-α and increased PGC-1α and IRS-1.

Diet Quality, Inflammation, and Quality of Life in Breast Cancer Survivors: A Cross-Sectional Analysis of Pilot Study Data

BackgroundModifiable lifestyle factors, such as diet quality, could reduce inflammation and improve quality of life (QOL) in breast cancer survivors, but data are inconclusive. ObjectiveTo determine whether diet quality, as measured by Healthy Eating Index-2010 (HEI-2010) score, is associated with inflammation, health status, or functional outcomes affecting QOL in survivors of early-stage breast cancer. DesignThis is a cross-sectional, secondary analysis of baseline data collected from breast cancer survivors after completion of primary therapy and before random assignment to a pilot nutritional intervention aimed at reducing side effects of aromatase inhibitor treatment. Participants/settingParticipants were 44 postmenopausal women with stage I to III endocrine receptor–positive breast cancer receiving outpatient care at a midwestern cancer center between November 2011 and October 2013. Main outcome measuresPrimary outcomes were serum proinflammatory cytokines (interleukin-6 [IL-6], IL-17, and tumor necrosis factor-α receptor 2 [TNFR-2]). Secondary outcomes included QOL measured by the Stanford Health and Disability Questionnaire and the Functional Assessment of Cancer Therapy–Breast with Endocrine Subscale. Statistical analyses performedPearson correlation coefficients (r) and linear regression models were used to evaluate the relationship of dietary variables with inflammatory cytokines and QOL measures. ResultsA higher overall HEI-2010 score (healthier diet) was associated with lower IL-6 (r=−0.46; P=0.002) and TNFR-2 (r=−0.41; P=0.006); however, associations were attenuated by body mass index (BMI) (IL=6 [r=−0.26; P=0.10]; TNFR-2 [r=−0.30; P=0.06]). In women with prior chemotherapy, a higher HEI-2010 score was strongly associated with lower IL-6 (r=−0.67; P=0.009) and TNFR-2 (r=−0.59; P=0.03) after BMI adjustment. There were no significant correlations between HEI-2010 score and QOL measures after adjustment for BMI. ConclusionsThese data suggest the need for more rigorous investigation into the relationship of diet quality, BMI, and inflammation in breast cancer survivors.

Nonalcoholic Fatty Liver Disease Is Exacerbated in High-Fat Diet-Fed Gnotobiotic Mice by Colonization with the Gut Microbiota from Patients with Nonalcoholic Steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is a serious liver disorder associated with the accumulation of fat and inflammation. The objective of this study was to determine the gut microbiota composition that might influence the progression of NAFLD. Germ-free mice were inoculated with feces from patients with nonalcoholic steatohepatitis (NASH) or from healthy persons (HL) and then fed a standard diet (STD) or high-fat diet (HFD). We found that the epididymal fat weight, hepatic steatosis, multifocal necrosis, and inflammatory cell infiltration significantly increased in the NASH-HFD group. These findings were consistent with markedly elevated serum levels of alanine transaminase, aspartate transaminase, endotoxin, interleukin 6 (IL-6), monocyte chemotactic protein 1 (Mcp1), and hepatic triglycerides. In addition, the mRNA expression levels of Toll-like receptor 2 (Tlr2), Toll-like receptor 4 (Tlr4), tumor necrosis factor alpha (Tnf-α), Mcp1, and peroxisome proliferator-activated receptor gamma (Ppar-γ) significantly increased. Only abundant lipid accumulation and a few inflammatory reactions were observed in group HL-HFD. Relative abundance of Bacteroidetes and Firmicutes shifted in the HFD-fed mice. Furthermore, the relative abundance of Streptococcaceae was the highest in group NASH-HFD. Nevertheless, obesity-related Lactobacillaceae were significantly upregulated in HL-HFD mice. Our results revealed that the gut microbiota from NASH Patients aggravated hepatic steatosis and inflammation. These findings might partially explain the NAFLD progress distinctly was related to different compositions of gut microbiota.

Covering the Cover

Covering the Cover

Chronic Brucella Infection Induces Selective and Persistent Interferon Gamma-Dependent Alterations of Marginal Zone Macrophages in the Spleen.

The spleen is known as an important filter for blood-borne pathogens that are trapped by specialized macrophages in the marginal zone (MZ): the CD209+ MZ macrophages (MZMs) and the CD169+ marginal metallophilic macrophages (MMMs). Acute systemic infection strongly impacts MZ populations and the location of T and B lymphocytes. This phenomenon has been linked to reduced chemokine secretion by stromal cells. Brucella spp. are the causative agent of brucellosis, a widespread zoonotic disease. Here, we used Brucella melitensis infection as a model to investigate the impact of chronic stealth infection on splenic MZ macrophage populations. During the late phase of Brucella infection, we observed a loss of both MZMs and MMMs, with a durable disappearance of MZMs, leading to a reduction of the ability of the spleen to take up soluble antigens, beads, and unrelated bacteria. This effect appears to be selective as every other lymphoid and myeloid population analyzed increased during infection, which was also observed following Brucella abortus and Brucella suis infection. Comparison of wild-type and deficient mice suggested that MZ macrophage population loss is dependent on interferon gamma (IFN-γ) receptor but independent of T cells or tumor necrosis factor alpha receptor 1 (TNF-αR1) signaling pathways and is not correlated to an alteration of CCL19, CCL21, and CXCL13 chemokine mRNA expression. Our results suggest that MZ macrophage populations are particularly sensitive to persistent low-level IFN-γ-mediated inflammation and that Brucella infection could reduce the ability of the spleen to perform certain MZM- and MMM-dependent tasks, such as antigen delivery to lymphocytes and control of systemic infection.

Frequency of TNFR1 36 A/G gene polymorphism in azoospermic infertile men: A case-control study

Tumor necrosis factor-alpha (TNF-α) is a multifunctional cytokine that regulates different cellular activities related to spermatogenesis. Tumor necrosis factor-alpha receptor 1 (TNFR1) mediates TNF-α activity and polymorphism in TNFR1 could lead to gene dysfunction and male infertility. The aim of this study is to determine the association of TNFR1 36 A/G polymorphism with the idiopathic azoospermia in Iranian population. This case-control study included 108 azoospermic and 119 fertile men. This research investigated the frequency of TNFR1 36 A/G polymorphism in cases who were idiopathic azoospermic men referred to Yazd Research and Clinical Center for Infertility, Iran in comparison with controls. polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) method was used to investigate the polymorphism in both case and control groups. PCR fragments were digested by Mspa1I enzyme and products were appeared by gel electrophoresis. The abundance of A→G was calculated in the azoospermic and healthy men. According to the present study, GG and AG genotypes frequency in the azoospermic men group were higher than the control group (OR= 2.298 (1.248-4.229), p=0.007), (OR=1.47 (0.869-2.498, p=0.149). Our findings also showed that G allele frequency in azoospermic men had significant difference compared to the control group (OR=2.302 (1.580-3.355), p<0.001). It seems that the GG genotype and G allele have an association with increased risk of non-obstructive azoospermia.

The effects of tumor necrosis factor-α (TNF-α) and IL-1 receptor antagonist (IL-1Ra) polymorphisms on recurrent abortion in Azari women.

Recurrent pregnancy loss (RPL) is a heterogeneous condition consisting of three or more consecutive abortions before the 20 weeks of gestation. The tumor necrosis factor alpha (TNF-α) gene plays a crucial role in immunology and inflammation responses. Interleukin 1 receptor antagonist (IL-1RN) is an important anti-inflammatory molecule which plays important roles in pregnancy. The aim of this study was to investigate effects of TNF-α and IL-1Ra polymorphisms on RPL in Azari women. The study participants consisted of 100 women with RPL from Iranian Azeri Turkish origin. The control group comprised 100 age and ethnically matched healthy women in the reproductive age. Genomic DNA was extracted from the whole blood and genotype determinations were performed using PCR amplification followed by restriction fragment length polymorphism (RFLP) analysis. No significant association was indicated between IL-1Ra and RPL among Iranian Azeri Turkish women. Unlike the homozygous state, significantly higher frequency of -857 C/T variant was seen in RPL patients than control subjects. Significantly lower frequency of wild type genotype was observed in RPL patients than of controls. Any association was found between the other TNF-α polymorphisms and RPL. TNF-α -857 C/C variant might represent protective effect against RPL and the -857 C/T variant might be a genetic risk factor for the occurrence of RPL. Invariant differences in the prevalence of -511 C/T and -31 C/T polymorphisms and IL-1RN VNTR between RPL patients.

Tumor necrosis factor-α receptor 1 contributes to ethanol-induced vascular reactive oxygen species generation and hypertension

We evaluated the contribution of tumor necrosis factor-α receptor 1 (TNFR1) to ethanol-induced hypertension and vascular oxidative stress and the possible role of perivascular adipose tissue (PVAT) in such responses. Male C57BL/6 wild-type (WT) or TNFR1-deficient mice (TNFR1−/−) were treated with ethanol (20% vol/vol) for 12 weeks. Ethanol induced an increase in blood pressure in WT mice and TNFR1−/− at 4 and 5 weeks of treatment, respectively. Treatment with ethanol increased tumor necrosis factor-α and interleukin-6 levels in aortas with or without PVAT (PVAT+ and PVAT−, respectively) from WT mice, but not TNFR1−/−. Ethanol increased superoxide anion (O2−) generation, thiobarbituric acid reactive substance concentration, and the activity of superoxide dismutase and catalase in aortas (PVAT− and PVAT+) from WT mice, but not TNFR1−/−. Conversely, ethanol consumption decreased the concentration of nitrate/nitrite in aortas (PVAT− and PVAT+) from WT mice, but not TNFR1−/−. Treatment with ethanol increased myeloperoxidase activity in aortas (PVAT− and PVAT+) from WT mice, but not TNFR1−/−. The major finding of our study is that TNFR1 contributes to ethanol-induced hypertension and oxidative stress in the vasculature. Additionally, TNFR1 plays a role in ethanol-induced increase in proinflammatory cytokines and neutrophils migration. However, PVAT does not counteract or aggravate the effects induced by ethanol.

TNF-α receptor 1 knockdown in the subfornical organ ameliorates sympathetic excitation and cardiac hemodynamics in heart failure rats.

In systolic heart failure (HF), circulating proinflammatory cytokines upregulate inflammation and renin-angiotensin system (RAS) activity in cardiovascular regions of the brain, contributing to sympathetic excitation and cardiac dysfunction. Important among these is the subfornical organ (SFO), a forebrain circumventricular organ that lacks an effective blood-brain barrier and senses circulating humors. We hypothesized that the tumor necrosis factor-α (TNF-α) receptor 1 (TNFR1) in the SFO contributes to sympathetic excitation and cardiac dysfunction in HF rats. Rats received SFO microinjections of a TNFR1 shRNA or a scrambled shRNA lentiviral vector carrying green fluorescent protein, or vehicle. One week later, some rats were euthanized to confirm the accuracy of the SFO microinjections and the transfection potential of the lentiviral vector. Other rats underwent coronary artery ligation (CL) to induce HF or a sham operation. Four weeks after CL, vehicle- and scrambled shRNA-treated HF rats had significant increases in TNFR1 mRNA and protein, NF-κB activity, and mRNA for inflammatory mediators, RAS components and c-Fos protein in the SFO and downstream in the hypothalamic paraventricular nucleus, along with increased plasma norepinephrine levels and impaired cardiac function, compared with vehicle-treated sham-operated rats. In HF rats treated with TNFR1 shRNA, TNFR1 was reduced in the SFO but not paraventricular nucleus, and the central and peripheral manifestations of HF were ameliorated. In sham-operated rats treated with TNFR1 shRNA, TNFR1 expression was also reduced in the SFO but there were no other effects. These results suggest a key role for TNFR1 in the SFO in the pathophysiology of systolic HF.NEW & NOTEWORTHY Activation of TNF-α receptor 1 in the subfornical organ (SFO) contributes to sympathetic excitation in heart failure rats by increasing inflammation and renin-angiotensin system activity in the SFO and downstream in the hypothalamic paraventricular nucleus. Cytokine receptors in the SFO may be a target for central intervention in cardiovascular conditions characterized by peripheral inflammation.

Drugs for Autoimmune Inflammatory Diseases: From Small Molecule Compounds to Anti-TNF Biologics.

Although initially described as an anti-tumor mediator, tumor necrosis factor-alpha (TNF) is generally considered as the master pro-inflammatory cytokine. It plays a crucial role in the pathogenesis of inflammatory diseases, such as rheumatoid arthritis (RA), inflammatory bowel disease, ankylosing spondylitis (AS), and psoriasis. Consequently, anti-TNF therapy has become mainstay treatment for autoimmune diseases. Historically, anti-inflammatory agents were developed before the identification of TNF. Salicylates, the active components of Willow spp., were identified in the mid-19th century for the alleviation of pain, fever, and inflammatory responses. Study of this naturally occurring compound led to the discovery of aspirin, which was followed by the development of non-steroidal anti-inflammatory drugs (NSAIDs) due to the chemical advances in the 19th–20th centuries. Initially, the most of NSAIDs were organic acid, but the non-acidic compounds were also identified as NSAIDs. Although effective in the treatment of inflammatory diseases, NSAIDs have some undesirable and adverse effect, such as ulcers, kidney injury, and bleeding in the gastrointestinal tract. In the past two decades, anti-TNF biologics were developed. Drugs belong to this class include soluble TNF receptor 2 fusion protein and anti-TNF antibodies. The introduction of anti-TNF therapeutics has revolutionized the management of autoimmune diseases, such as RA, psoriatic arthritis (PsA), plaque psoriasis (PP), AS, CD and ulcerative colitis (UC). Nevertheless, up to 40% of patients have no response to anti-TNF treatment. Furthermore, this treatment is associated with some adverse effects such as increased risk of infection, and even triggered the de novo development of autoimmune diseases. Such harmful effect of anti-TNF treatment is likely caused by the global inhibition of TNF biological functions. Therefore, specific inhibition of TNF receptor (TNFR1 or TNFR2) may represent a safer and more effective treatment, as proposed by some recent studies. In this review article, the historical development of anti-inflammatory drugs after World War II as briefly described above will be reviewed and analyzed. The future trend in the development of novel TNF receptor-targeting therapeutics will be discussed in the context of latest progress in the research of TNF biology.

Tumor necrosis factor receptor 2 as a possible marker of COPD in smokers and ex-smokers

IntroductionOxidative stress and systemic inflammation are higher in smokers and patients with COPD; however, markers that may help differentiate between smokers and patients with COPD have not yet been identified. We hypothesized that tumor necrosis factor-alpha receptor (TNFR) and soluble form of the receptor for advanced glycation end products (sRAGE) can be indicators of COPD in asymptomatic patients.Patients and methodsWe evaluated 32 smokers (smoking history >10 pack-years), 32 patients with mild/moderate COPD (smokers and ex-smokers), and 32 never smokers. Concentrations of C-reactive protein (CRP), interleukin (IL)-6, TNFR1 and TNFR2, advanced glycation end products (AGEs), and the sRAGE were measured in serum.ResultsThere were higher CRP and AGEs concentrations in smokers and in patients with COPD (P<0.001 and P=0.01, respectively) compared to controls, without statistical difference between smokers and patients with COPD. Concentrations of sRAGE, IL-6, and TNFR1 did not differ between study groups. TNFR2 was significantly higher in patients with COPD than in smokers (P=0.004) and controls (P=0.004), and the presence of COPD (P=0.02) and CRP (P=0.001) showed a positive association with TNFR2. Positive associations for smoking (P=0.04), CRP (P=0.03), and IL-6 (P=0.03) with AGEs were also found. The interaction variable (smoking × COPD) showed a positive association with IL-6.ConclusionOur data suggest that TNFR2 may be a possible marker of COPD in asymptomatic smokers and ex-smokers. Although smokers and patients with early COPD presented other increased systemic inflammation markers (eg, CRP) and oxidative stress (measured by AGEs), they did not differentiate smokers from COPD.