Effect of Etanercept on Insulin Sensitivity in Nine Patients with Psoriasis

Metabolic syndrome is associated to chronic low grade inflammation, characterized by increased levels of inflammatory cytokines, such as Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6). In particular, TNF-α causes a decrease in the insulin-stimulated kinases related to the early phases of the insulin cascade, thereby leading to insulin resistance. Etanercept is a human fusion protein used in the treatment of psoriasis and inflammatory arthritis. It blocks inflammatory response by interfering in the binding of TNF-α to its receptors. The aim of this case report study is to verify the effect of Etanercept on insulin sensitivity, lipid profile and inflammatory status in psoriatic patients. Nine psoriatic patients with stable, active, plaque type psoriasis were enrolled and treated with Etanercept for 24 weeks. We found an improvement in the metabolic assessment with a significant reduction of insulin plasma levels. In particular, this treatment allows to maintain their euglycemic state with lower insulin plasma levels, as confirmed by the improved Homeostasis Model Assessment (HOMA) index. We conclude that Etanercept, probably acting on inflammation, improves insulin sensitivity in psoriatic subjects.

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Insulin resistance and liver histopathology in metabolically unhealthy subjects do not correlate with the hepatic abundance of NLRP3 inflammasome nor circulating IL-1β levels

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001975 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001975

Author(s):

Nicolas Quezada ◽

Ilse Valencia ◽

Javiera Torres ◽

Gregorio Maturana ◽

Jaime Cerda ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Liver Damage ◽

Nlrp3 Inflammasome ◽

Low Grade ◽

Model Assessment ◽

Alcoholic Fatty Liver ◽

Protein Levels ◽

Liver Histopathology ◽

Inflammatory Status

IntroductionSystemic chronic low-grade inflammation has been linked to insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). NOD-like receptor protein 3 (NLRP3) inflammasome and its final product, interleukin (IL)-1β, exert detrimental effects on insulin sensitivity and promote liver inflammation in murine models. Evidence linking hepatic NLRP3 inflammasome, systemic IR and NASH has been scarcely explored in humans. Herein, we correlated the hepatic abundance of NLRP3 inflammasome components and IR and NASH in humans.Research design and methodsMetabolically healthy (MH) (n=11) and metabolically unhealthy (MUH) (metabolic syndrome, n=21, and type 2 diabetes, n=14) subjects were recruited. Insulin sensitivity (homeostatic model assessment of IR (HOMA-IR) and Oral Glucose Sensitivity (OGIS120)), glycemic (glycated hemoglobin), and lipid parameters were determined by standard methods. Plasma cytokines were quantified by Magpix. Hepatic NLRP3 inflammasome components were determined at the mRNA and protein levels by reverse transcription–quantitative PCR and western blot, respectively. Liver damage was assessed by histological analysis (Non-alcoholic Fatty Liver Disease Activity Score (NAS) and Steatosis, Inflammatory Activity, and Fibrosis (SAF) scores). IR and liver histopathology were correlated with NLRP3 inflammasome components as well as with liver and plasma IL-1β levels.ResultsBody Mass Index, waist circumference, and arterial hypertension frequency were significantly higher in MUH subjects. These patients also had increased high-sensitivity C reactive protein levels compared with MH subjects. No differences in the plasma levels of IL-1β nor the hepatic content of Nlrp3, apoptosis-associated speck-like (Asc), Caspase-1, and IL-1β were detected between MUH and MH individuals. MUH subjects had significantly higher NAS and SAF scores, indicating more severe liver damage. However, histological severity did not correlate with the hepatic content of NLRP3 inflammasome components nor IL-1β levels.ConclusionOur results suggest that NLRP3 inflammasome activation is linked neither to IR nor to the inflammatory status of the liver in MUH patients.

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Differential effect of selective block of α2-adrenoreceptors on plasma levels of tumour necrosis factor-α, interleukin-6 and corticosterone induced by bacterial lipopolysaccharide in mice

Journal of Endocrinology ◽

10.1677/joe.0.1440457 ◽

1995 ◽

Vol 144 (3) ◽

pp. 457-462 ◽

Cited By ~ 77

Author(s):

G Haskó ◽

I J Elenkov ◽

V Kvetan ◽

E S Vizi

Keyword(s):

Tumour Necrosis Factor ◽

Interleukin 6 ◽

Plasma Levels ◽

Tumour Necrosis ◽

Endotoxin Shock ◽

Bacterial Lipopolysaccharide ◽

Tumour Necrosis Factor Α ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

Abstract The effect of selective block of α2-adrenoreceptors on plasma levels of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and corticosterone induced by bacterial lipopolysaccharide (LPS) was investigated in mice using ELISA and RIA. It was found that the LPS-induced TNF-α response was significantly blunted in mice pretreated with CH-38083, a novel and highly selective α2-adrenoreceptor antagonist (the α2/α1 ratio is >2000). In contrast, LPS-induced increases in both corticosterone and IL-6 plasma levels were further increased by CH-38083. Since it has recently been shown that the selective block of α2-adrenoreceptors located on noradrenergic axon terminals resulted in an increase in the release of noradrenaline (NA), both in the central and peripheral nervous systems, and, in our experiments, that propranolol prevented the effect of α2-adrenoreceptor blockade on TNF-α plasma levels induced by LPS, it seems likely that the excessive stimulation by NA of β-adrenoreceptors located on cytokine-secreting immune cells is responsible for this action. Since it is generally accepted that increased production of TNF-α is involved in the pathogenesis of inflammation and endotoxin shock on the one hand, and corticosterone and even IL-6 are known to possess anti-inflammatory properties on the other hand, it is suggested that the selective block of α2-adrenoreceptors might be beneficial in the treatment of inflammation and/or endotoxin shock. Journal of Endocrinology (1995) 144, 457–462

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TNF-α induced bronchial vasoconstriction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.3.h946 ◽

2000 ◽

Vol 279 (3) ◽

pp. H946-H951 ◽

Cited By ~ 22

Author(s):

Elizabeth M. Wagner

Keyword(s):

Bronchial Artery ◽

Autologous Blood ◽

Inflammatory Status ◽

Tnf Α ◽

In Vitro Systems ◽

Essential Function ◽

Factor Α ◽

Necrosis Factor ◽

Airways Inflammation

The pro-inflammatory characteristics of tumor necrosis factor-α (TNF-α) have been extensively characterized in in vitro systems. Furthermore, this cytokine has been shown to play a pivotal role in airways inflammation in asthma. Since the airway vasculature also performs an essential function in inflammatory cell transit to the airways, experiments were performed to determine the effects of TNF-α on bronchial vascular resistance (BVR). In anesthetized, ventilated sheep, the bronchial artery (BA) was cannulated and perfused with autologous blood. BVR was defined as inflow pressure/flow and averaged 6.3 ± 0.2 mmHg · ml−1 · min−1 (±SE) for the 25 sheep studied. Recombinant human TNF-α (10 μg for 20 or 40 min) infused directly into the BA resulted in a significant decrease in BVR to 87% of baseline ( P < 0.05). This vasodilation was followed by a reversal of tone by 120 min and a sustained increase in BVR to 126% of baseline ( P < 0.05). Since others have shown TNF-α caused coronary vasoconstriction through endothelial release of endothelin-1 (ET-1), an ET-1 antagonist was used to block bronchial vasoconstriction. BQ-123, a selective ETA receptor antagonist, was delivered to the bronchial vasculature prior to TNF-α challenge. Attenuation of bronchial vasoconstriction was observed at 120 min ( P < 0.03). Thus TNF-α causes bronchial vasoconstriction by the secondary release of ET-1. Although TNF-α exerts pro-inflammatory actions on most cells of the airways, vasoactive properties of this cytokine likely further contribute to the inflammatory status of the airways.

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Obesity-Induced TNFα and IL-6 Signaling: The Missing Link between Obesity and Inflammation—Driven Liver and Colorectal Cancers

Cancers ◽

10.3390/cancers11010024 ◽

2018 ◽

Vol 11 (1) ◽

pp. 24 ◽

Cited By ~ 30

Author(s):

Lara Kern ◽

Melanie Mittenbühler ◽

Anna Vesting ◽

Anna Ostermann ◽

Claudia Wunderlich ◽

...

Keyword(s):

Proinflammatory Cytokines ◽

Insulin Action ◽

Immune Cell ◽

Colorectal Cancers ◽

Low Grade ◽

Current State ◽

Immune Cell Subsets ◽

Factor Α ◽

Low Grade Inflammation ◽

Necrosis Factor

Obesity promotes the development of numerous cancers, such as liver and colorectal cancers, which is at least partly due to obesity-induced, chronic, low-grade inflammation. In particular, the recruitment and activation of immune cell subsets in the white adipose tissue systemically increase proinflammatory cytokines, such as tumor necrosis factor α (TNFα) and interleukin-6 (IL-6). These proinflammatory cytokines not only impair insulin action in metabolic tissues, but also favor cancer development. Here, we review the current state of knowledge on how obesity affects inflammatory TNFα and IL-6 signaling in hepatocellular carcinoma and colorectal cancers.

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β-Carotene Concentration and Its Association with Inflammatory Biomarkers in Spanish Schoolchildren

Annals of Nutrition and Metabolism ◽

10.1159/000479009 ◽

2017 ◽

Vol 71 (1-2) ◽

pp. 80-87 ◽

Cited By ~ 7

Author(s):

Elena Rodríguez-Rodríguez ◽

Ana M. López-Sobaler ◽

Beatriz Navia ◽

Pedro Andrés ◽

Ana I. Jiménez-Ortega ◽

...

Keyword(s):

High Sensitivity ◽

Inflammatory Biomarkers ◽

Reactive Protein ◽

Inflammatory Status ◽

Tnf Α ◽

Hs Crp ◽

Α Level ◽

Factor Α ◽

Β Carotene ◽

Necrosis Factor

Aim: To examine the correlation between inflammatory biomarkers and plasma β-carotene levels in children. Methods: A total of 564 Spanish schoolchildren aged 9-12 were observed and studied. Plasma β-carotene levels were assessed by HPLC. A β-carotene level <4.83 µg/dL (0.09 µmol/L) was considered deficient. Plasma tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured by immunoenzyme assays. Serum high-sensitivity C-reactive protein (hs-CRP) was tested by immunonephelometry. Results: Subjects who were β-carotene-deficient (23.1% of the studied children) had higher IL-6 levels than subjects with normal β-carotene concentrations. The log-IL-6 and log-hs-CRP concentrations, but not the log-TNF-α level, were strongly and inversely related to the plasma log-β-carotene level (taking into account log-age, energy intake, log-triglycerides, gender, log-body mass index, log-β-carotene intake, energy from lipids and cholesterol as covariables). When the 3 inflammatory biomarkers were introduced into the regression model along with the corresponding covariables, only the log-IL-6 level was related to the plasma log-β-carotene level (β = -0.505 ± 0.078; p < 0.001). Conclusions: Inflammatory status, in particular IL-6 levels, appears to be negatively associated with plasma β-carotene levels in schoolchildren.

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The self-nanoemulsifying drug delivery system of Petiveria alliacea extract reduced the homeostatic model assessment-insulin resistance value, interleukin-6, and tumor necrosis factor-α level in diabetic rat models

Veterinary World ◽

10.14202/vetworld.2021.3229-3234 ◽

2021 ◽

pp. 3229-3234

Author(s):

Arifa Mustika ◽

Nurmawati Fatimah ◽

Gadis Meinar Sari

Keyword(s):

Insulin Resistance ◽

Leaf Extract ◽

Diabetic Rat ◽

Model Assessment ◽

Tnf Α ◽

Significant Difference ◽

Petiveria Alliacea ◽

Homeostatic Model Assessment ◽

Factor Α ◽

Necrosis Factor

Background and Aim: Metaflammation plays a significant role in the pathogenesis, development, and complication of diabetes mellitus (DM). This inflammation is associated with insulin resistance. Therefore, the inflammatory pathways have been targeted for pharmacological treatment. Petiveria alliacea can decrease blood glucose levels and has anti-inflammatory and antioxidant activities; however, there are still insufficient data regarding its efficacy for the treatment of DM. This study aimed to investigate the effect of the self-nanoemulsifying drug delivery system (SNEDDS) of P. alliacea leaf extract on the homeostatic model assessment (HOMA)-insulin resistance (IR) value and interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) levels in a streptozotocin (STZ)-induced diabetic rat model. Materials and Methods: Thirty-five diabetic rat models were randomly divided into five groups. The first group received the SNEDDS of P. alliacea leaf extract at a dose of 50 mg/kg body weight (BW), the second group received it at a dose of 100 mg/kg BW, the third group received it at a dose of 200 mg/kg BW, the fourth group received 18 mg of metformin, and the fifth group only received the SNEDDS formula. The treatment was administered once a day, orally, for 14 days. On the 15th day after treatment, the rats were sacrificed to obtain blood samples for cardiac examination. The IL-6, TNF-α, and insulin levels in the serum were measured using the enzyme-linked immunosorbent assay method. The HOMA-IR value was calculated using a formula. Results: The mean IL-6 and TNF-α levels were low in the group that received the SNEDDS of P. alliacea leaf extract. There was no significant difference in the insulin level in all treatment and control groups. However, a significant difference in the HOMA-IR value was noted between the group that received the SNEDDS of P. alliacea leaf extract and metformin and the group that did not receive treatment (p<0.05). Conclusion: The SNEDDS of P. alliacea leaf extract reduced the HOMA-IR value and suppressed the TNF-α and IL-6 levels in the STZ-induced diabetic rat model.

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Lipopolysaccharide influence on leptin hormone and tumor necrosis factor-alpha release from human adipose tissue

European Journal of Inflammation ◽

10.1177/2058739218774975 ◽

2018 ◽

Vol 16 ◽

pp. 205873921877497

Author(s):

Sa’ad Al-Lahham ◽

Nidal Jaradat ◽

Malik Al-Qub ◽

Abdallah Hamayel ◽

Abdalrahman Assaassa ◽

...

Keyword(s):

Adipose Tissue ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Ex Vivo ◽

Enzyme Linked Immunosorbent Assay ◽

Low Grade ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Low Grade Inflammation ◽

Necrosis Factor

Obesity is associated with low-grade inflammation that originates mainly from adipose tissue. This is implicated in the pathogenesis of type-2 diabetes and cardiovascular diseases. Strong evidence indicates that chronically elevated systemic low-grade lipopolysaccharide (LPS), elicits low-grade inflammation. However, evidence on LPS effect on adipokines’ level, such as leptin, is scarce, and it has never been investigated ex vivo in human subcutaneous adipose tissue (SAT) and therefore we aim to investigate this. To achieve our aim, SAT explants were obtained from 12 patients (50% males) and were treated with/without LPS. Protein concentration was determined by enzyme-linked immunosorbent assay (ELISA). We found that the average age and body mass index (BMI) of included patients were 58.6 years and 28.6 kg/m2, respectively. LPS induced significantly (~3×, P < 0.0001) the secretion of tumor necrosis factor (TNF)-α from SAT, and it was not associated with age or BMI. However, leptin secretion was inhibited slightly (~20%), but significantly. Interestingly, leptin release was significantly inhibited (~50%) in SAT from lean but not from obese patients, and there was an association between leptin response and BMI (R = 0.8), but no association with age. In this study, we found, for the first time, that LPS suppresses the release of leptin hormone from SAT obtained from lean patients, while it induces TNF-α release. Our findings provide extra evidence and confirm earlier studies regarding the role of LPS in low-grade inflammation. Further investigations are essential to identify factors that inhibit LPS passage through intestinal barrier in order to prevent or reduce the development of obesity and its associated chronic diseases.

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Effect of TNF-Alpha on Caveolin-1 Expression and Insulin Signaling During Adipocyte Differentiation and in Mature Adipocytes

Cellular Physiology and Biochemistry ◽

10.1159/000430314 ◽

2015 ◽

Vol 36 (4) ◽

pp. 1499-1516 ◽

Cited By ~ 15

Author(s):

Sara Palacios-Ortega ◽

Maider Varela-Guruceaga ◽

Miriam Algarabel ◽

Fermín Ignacio Milagro ◽

J. Alfredo Martínez ◽

...

Keyword(s):

Glucose Uptake ◽

Insulin Signaling ◽

Adipocyte Differentiation ◽

Central Component ◽

Low Grade ◽

Caveolin 1 ◽

Tnf Α ◽

Uptake Assay ◽

Factor Α ◽

Low Grade Inflammation

Background/Aims: Tumor necrosis factor-α (TNF-α)-mediated chronic low-grade inflammation of adipose tissue is associated with obesity and insulin resistance. Caveolin-1 (Cav-1) is the central component of adipocyte caveolae and has an essential role in the regulation of insulin signaling. The effects of TNF-α on Cav-1 expression and insulin signaling during adipocyte differentiation and in mature adipocytes were studied. Methods: 3T3-L1 cells were differentiated (21 days) in the presence TNF-α (10 ng/mL) and mature adipocytes were also treated with TNF-α for 48 hours. Cav-1 and insulin receptor (IR) gene methylation were determined as well as Cav-1, IR, PKB/AKT-2 and Glut-4 expression and activation by real time RT-PCR and western blot. Baseline and insulin-induced glucose uptake was measured by the 2-[C14]-deoxyglucose uptake assay. Results: TNF-α slowed down the differentiation program, hindering the expression of some insulin signaling intermediates without fully eliminating insulin-mediated glucose uptake. In mature adipocytes, TNF-α did not compromise lipid-storage capacity, but downregulated the expression of the insulin signaling intermediates, totally blocking insulin-mediated glucose uptake. Insulin sensitivity correlated with the level of activated phospho-Cav-1 in both situations, strongly suggesting the direct contribution of Cav-1 to the maintenance of this physiological response. Conclusion: Cav-1 activation by phosphorylation seems to be essential for the maintenance of an active and insulin-sensitive glucose uptake.

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Tumor Necrosis Factor α and Interleukin-1β Acutely Inhibit AgRP Neurons in the Arcuate Nucleus of the Hypothalamus

International Journal of Molecular Sciences ◽

10.3390/ijms21238928 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8928

Author(s):

Fernanda M. Chaves ◽

Naira S. Mansano ◽

Renata Frazão ◽

Jose Donato

Keyword(s):

Tumor Necrosis Factor ◽

Interleukin 6 ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Interleukin 1Β ◽

Low Grade ◽

Membrane Excitability ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

Obesity-associated low-grade inflammation favors weight gain, whereas systemic infection frequently leads to anorexia. Thus, inflammatory signals can either induce positive or negative energy balance. In this study, we used whole-cell patch-clamp to investigate the acute effects of three important proinflammatory cytokines, tumor necrosis factor α (TNF-α), interleukin-6, and interleukin-1β (IL-1β) on the membrane excitability of agouti-related peptide (AgRP)- or proopiomelanocortin (POMC)-producing neurons. We found that both TNF-α and IL-1β acutely inhibited the activity of 35–42% of AgRP-producing neurons, whereas very few POMC neurons were depolarized by TNF-α. Interleukin-6 induced no acute changes in the activity of AgRP or POMC neurons. Our findings indicate that the effect of TNF-α and IL-1β, especially on the activity of AgRP-producing neurons, may contribute to inflammation-induced anorexia observed during acute inflammatory conditions.

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Longevity-Associated Variant of BPIFB4 Mitigates Monocyte-Mediated Acquired Immune Response

The Journals of Gerontology Series A ◽

10.1093/gerona/glz036 ◽

2019 ◽

Vol 74 (Supplement_1) ◽

pp. S38-S44 ◽

Cited By ~ 7

Author(s):

Elena Ciaglia ◽

Francesco Montella ◽

Anna Maciag ◽

Pasqualina Scala ◽

Anna Ferrario ◽

...

Keyword(s):

Mononuclear Cells ◽

Therapeutic Potential ◽

Human Monocyte ◽

Peripheral Blood Mononuclear ◽

Inflammatory Status ◽

Tnf Α ◽

Cytokine Tumor Necrosis Factor ◽

Pkc Alpha ◽

Factor Α ◽

Necrosis Factor

Abstract One of the basis of exceptional longevity is the maintaining of the balance between inflammatory and anti-inflammatory networks. The monocyte-macrophages activation plays a major role in tuning the immune responses, by oscillating between patrolling-protective to inflammatory status. Longevity-associated variant (LAV) of bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) activates calcium, PKC-alpha, and eNOS, rescuing endothelial dysfunction in aged mice and inducing revascularization. The BPIFB4’s increment in serum of healthy long-living individuals (LLIs) compared to nonhealthy ones, its therapeutic potential in improving vascular homeostasis, which depends on immune system, together with its expression in bone marrow myeloid cells, suggests that LAV-BPIFB4 may improve immune regulation. Here we show that human monocytes exposed to LAV-BPIFB4 protein increased co-stimulatory molecules in resting state and reduced pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) after activating stimuli. Accordingly, a low percentage of CD69+ activated lymphocytes are found among LAV-BPIFB4-treated peripheral blood mononuclear cells (PBMCs). Moreover, human monocyte-derived dendritic cells (DCs) generated in presence of LAV-BPIFB4 secreted higher anti-(IL-10 and TGF-β) and lower pro-inflammatory (TNF-α and IL-1β) cytokines. Accordingly, LLIs’ plasma showed higher levels of circulating IL-10 and of neutralizing IL-1 receptor antagonist (IL-1RA) compared to controls. Thus, LAV-BPIFB4 effects on myeloid compartment could represent one example of a genetic predisposition carried by LLIs to protect from immunological dysfunctions.

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