scholarly journals Concomitant Assessment of Monocyte HLA-DR Expression and Ex Vivo TNF-α Release as Markers of Adverse Outcome after Various Injuries—Insights from the REALISM Study

2021 ◽  
Vol 11 (1) ◽  
pp. 96
Author(s):  
Frank Bidar ◽  
Maxime Bodinier ◽  
Fabienne Venet ◽  
Anne-Claire Lukaszewicz ◽  
Karen Brengel-Pesce ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Secondary Infection ◽  
Human Leukocyte ◽  
Severe Trauma ◽  
Adverse Outcomes ◽  
Severe Injuries ◽  
Icu Patients ◽  
Tnf Α ◽  
Two Parameters ◽  
Factor Α

Intensive care unit (ICU) patients develop an altered host immune response after severe injuries. This response may evolve towards a state of persistent immunosuppression that is associated with adverse clinical outcomes. The expression of human leukocyte antigen DR on circulating monocytes (mHLA-DR) and ex vivo release of tumor necrosis factor α (TNF-α) by lipopolysaccharide-stimulated whole blood are two related biomarkers offered to characterize this phenomenon. The purpose of this study was to concomitantly evaluate the association between mHLA-DR and TNF-α release and adverse clinical outcome (i.e., death or secondary infection) after severe trauma, sepsis or surgery in a cohort of 353 ICU patients. mHLA-DR and TNF-α release was similarly and significantly reduced in patients whatever the type of injury. Persistent decreases in both markers at days 5–7 (post-admission) were significantly associated with adverse outcomes. Overall, mHLA-DR (measured by flow cytometry) appears to be a more robust and standardized parameter. Each marker can be used individually as a surrogate of immunosuppression, depending on center facilities. Combining these two parameters could be of interest to identify the most immunosuppressed patients presenting with a high risk of worsening. This last aspect deserves further exploration.

Epinephrine inhibits endotoxin-induced IL-1β production: roles of tumor necrosis factor-α and IL-10

1997 ◽  
Vol 273 (6) ◽  
pp. R1885-R1890 ◽  
Author(s):  
Tom Van Der Poll ◽  
Stephen F. Lowry
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Ex Vivo ◽  
Systemic Infection ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor ◽  
Dose Dependent Decrease ◽  
Factor Α ◽  
Necrosis Factor

Epinephrine has been found to inhibit the production of the proinflammatory cytokine tumor necrosis factor (TNF)-α and to enhance the production of anti-inflammatory cytokine interleukin (IL)-10. To determine the effect of epinephrine on IL-1β production, the following experiments were performed: 1) blood obtained from subjects at 4–21 h after the start of a continuous infusion of epinephrine (30 ng ⋅ kg−1⋅ min−1) produced less IL-1β after ex vivo stimulation with lipopolysaccharide (LPS), compared with blood drawn from subjects infused with saline; 2) in whole blood in vitro, epinephrine caused a dose-dependent decrease in LPS-induced IL-1β production, which was likely mediated via adrenergic receptors; and 3) inhibition of TNF and enhancement of IL-10 both contributed to epinephrine-induced inhibition of IL-1β production. Epinephrine, either endogenously produced or administered as a component of sepsis treatment, may attenuate excessive activity of proinflammatory cytokines early in the course of systemic infection.

scholarly journals Atherosclerosis as Pathogenetic Substrate for Sars-Cov2 Cytokine Storm

2020 ◽  
Vol 9 (7) ◽  
pp. 2095 ◽  
Author(s):  
Mattia Vinciguerra ◽  
Silvia Romiti ◽  
Khalil Fattouch ◽  
Antonio De Bellis ◽  
Ernesto Greco
Keyword(s):  
Immune System ◽  
Viral Replication ◽  
Multiorgan Failure ◽  
Severe Infection ◽  
Adverse Outcomes ◽  
Alveolar Cells ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor ◽  
Plasmatic Concentration

The severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) outbreak is a public health emergency affecting different regions around the world. The lungs are often damaged due to the presence of Sars-CoV-2 binding receptor ACE2 on epithelial alveolar cells. Severity of infection varies from complete absence of symptomatology to more aggressive symptoms, characterized by sudden acute respiratory distress syndrome (ARDS), multiorgan failure, and sepsis, requiring treatment in intensive care unit (ICU). It is not still clear why the immune system is not able to efficiently suppress viral replication in a small percentage of patients. It has been documented as pathological conditions affecting the cardiovascular system, strongly associated to atherosclerotic progression, such as heart failure (HF), coronary heart disease (CHD), hypertension (HTN) and diabetes mellitus (DM), could serve as predictive factors for severity and susceptibility during Sars-CoV-2 infection. Atherosclerotic progression, as a chronic inflammation process, is characterized by immune system dysregulation leading to pro-inflammatory patterns, including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and IL-1β. Reviewing immune system and inflammation profiles in atherosclerosis and laboratory results reported in severe COVID-19 infections, we hypothesized a pathogenetic correlation. Atherosclerosis may be an ideal pathogenetic substrate for high viral replication ability, leading to adverse outcomes, as reported in patients with cardiovascular factors. The level of atherosclerotic progression may affect a different degree of severe infection; in a vicious circle, feeding itself, Sars-CoV-2 may exacerbate atherosclerotic evolution due to excessive and aberrant plasmatic concentration of cytokines.

scholarly journals Effect of the proinflammatory cytokine TNF-α on intestinal riboflavin uptake: inhibition mediated via transcriptional mechanism(s)

2018 ◽  
Vol 315 (5) ◽  
pp. C653-C663 ◽  
Author(s):  
Kasin Yadunandam Anandam ◽  
Omar A. Alwan ◽  
Veedamali S. Subramanian ◽  
Padmanabhan Srinivasan ◽  
Rubina Kapadia ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Significant Inhibition ◽  
Mrna Levels ◽  
In Vivo Models ◽  
Uptake Inhibition ◽  
Tnf Α ◽  
Vitro Model ◽  
Factor Α

Riboflavin (RF), is essential for normal cellular metabolism/function. Intestinal RF absorption occurs via a specific carrier-mediated process that involves the apical transporter RFVT-3 ( SLC52A3) and the basolateral RFVT-1 (SLC52A1). Previously, we characterized different cellular/molecular aspects of the intestinal RF uptake process, but nothing is known about the effect of proinflammatory cytokines on the uptake event. We addressed this issue using in vitro, ex vivo, and in vivo models. First, we determined the level of mRNA expression of the human (h)RFVT-3 and hRFVT-1 in intestinal tissue of patients with inflammatory bowel disease (IBD) and observed a markedly lower level compared with controls. In the in vitro model, exposing Caco-2 cells to tumor necrosis factor-α (TNF-α) led to a significant inhibition in RF uptake, an effect that was abrogated upon knocking down TNF receptor 1 (TNFR1). The inhibition in RF uptake was associated with a significant reduction in the expression of hRFVT-3 and -1 protein and mRNA levels, as well as in the activity of the SLC52A3 and SLC52A1 promoters. The latter effects appear to involve Sp1 and NF-κB sites in these promoters. Similarly, exposure of mouse small intestinal enteroids and wild-type mice to TNF-α led to a significant inhibition in physiological and molecular parameters of intestinal RF uptake. Collectively, these findings demonstrate that exposure of intestinal epithelial cells to TNF-α leads to inhibition in RF uptake and that this effect is mediated, at least in part, via transcriptional mechanism(s). These findings may explain the significantly low RF levels observed in patients with IBD.

scholarly journals Staphylococcus aureus α-Toxin Induces Inflammatory Cytokines via Lysosomal Acid Sphingomyelinase and Ceramides

2017 ◽  
Vol 43 (6) ◽  
pp. 2170-2184 ◽  
Author(s):  
Jie Ma ◽  
Erich Gulbins ◽  
Michael J. Edwards ◽  
Charles C. Caldwell ◽  
Martin Fraunholz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Confocal Microscopy ◽  
Inflammatory Cytokines ◽  
Cathepsin B ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Clinical Problem ◽  
Acid Sphingomyelinase ◽  
Tnf Α ◽  
Factor Α

Background/Aims: Staphylococcus aureus (S. aureus) infections are a major clinical problem and range from mild skin and soft-tissue infections to severe and even lethal infections such as pneumonia, endocarditis, sepsis, osteomyelitis, and toxic shock syndrome. Toxins that are released from S. aureus mediate many of these effects. Here, we aimed to identify molecular mechanisms how α-toxin, a major S. aureus toxin, induces inflammation. Methods: Macrophages were isolated from the bone marrow of wildtype and acid sphingomyelinase-deficient mice, stimulated with S. aureus α-toxin and activation of the acid sphingomyelinase was quantified. The subcellular formation of ceramides was determined by confocal microscopy. Release of cathepsins from lysosomes, activation of inflammasome proteins and formation of Interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNF-α) were analyzed by western blotting, confocal microscopy and ELISA. Results: We demonstrate that S. aureus α-toxin activates the acid sphingomyelinase in ex vivo macrophages and triggers a release of ceramides. Ceramides induced by S. aureus α-toxin localize to lysosomes and mediate a release of cathepsin B and D from lysosomes into the cytoplasm. Cytosolic cathepsin B forms a complex with Nlrc4. Treatment of macrophages with α-toxin induces the formation of IL-1β and TNF-α. These events are reduced or abrogated, respectively, in cells lacking the acid sphingomyelinase and upon treatment of macrophages with amitriptyline, a functional inhibitor of acid sphingomyelinase. Pharmacological inhibition of cathepsin B prevented activation of the inflammasome measured as release of IL-1β, while the formation of TNF-α was independent of cathepsin B. Conclusion: We demonstrate a novel mechanism how bacterial toxins activate the inflammasome and mediate the formation and release of cytokines: S. aureus α-toxin triggers an activation of the acid sphingomyelinase and a release of ceramides resulting in the release of lysosomal cathepsin B and formation of pro-inflammatory cytokines.

Dendritic cell precursor populations of mouse blood: identification of the murine homologues of human blood plasmacytoid pre-DC2 and CD11c+ DC1 precursors

Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1453-1459 ◽  
Author(s):  
Meredith O'Keeffe ◽  
Hubertus Hochrein ◽  
David Vremec ◽  
Bernadette Scott ◽  
Paul Hertzog ◽  
...  
Keyword(s):  
Human Blood ◽  
Ex Vivo ◽  
Mouse Blood ◽  
Surface Phenotype ◽  
Isolation And Characterization ◽  
Tnf Α ◽  
Close Relationship ◽  
Factor Α ◽  
And Function

Immature and predendritic cells (pre-DCs) of human blood are the most readily accessible human DC sources available for study ex vivo. Murine homologues of human blood DCs have not been described. We report the isolation and characterization of 2 populations of precursor DCs in mouse blood. Mouse blood cells with the surface phenotype CD11cloCD11b−CD45RAhi closely resemble human plasmacytoid cells (or pre-DC2) by morphology and function. On stimulation with oligonucleotides containing CpG motifs (CpG), these cells make large amounts of type 1 interferons and rapidly develop into DCs that bear CD8, though they may be distinct from the CD8+ DCs in the unstimulated mouse. A second population of cells with the surface phenotype CD11c+CD11b+CD45RA− closely resembles the immediate precursors of pre-DC1, rapidly transforming into CD8− DCs after tumor necrosis factor-α (TNF-α) stimulation. These findings indicate the close relationship between human and mouse DCs, provided cells are obtained directly from equivalent source materials.

Evidence supporting involvement of leukotrienes in LPS-induced hypothermia in mice

1999 ◽  
Vol 276 (1) ◽  
pp. R52-R58 ◽  
Author(s):  
Lada Paul ◽  
Vadim Fraifeld ◽  
Jacob Kaplanski
Keyword(s):  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Ex Vivo ◽  
Induced Hypothermia ◽  
Significant Elevation ◽  
Hypothermic Effect ◽  
Tnf Α ◽  
Α Level ◽  
Factor Α ◽  
Necrosis Factor

The aim of the present study was to examine a possible involvement of leukotrienes (LTs) in lipopolysaccharide (LPS)-induced body temperature (Tb) response. We examined the effect of MK-886, an inhibitor of LT synthesis, on changes in Tb, plasma tumor necrosis factor-α (TNF-α), hypothalamic LT, and PGE2 production. Intraperitoneal injection of LPS (50 μg/mouse) led to a decrease in Tb starting 1 h after the injection. The hypothermic effect of LPS was accompanied by a significant elevation in TNF-α level in plasma and in LT and PGE2 production by ex vivo-incubated hypothalamus. MK-886 (1 mg/kg ip) administered 4 h before LPS efficaciously prevented LPS-induced hypothermia in mice. Pretreatment of mice with MK-886 did not alter the LPS-stimulated increase in plasma TNF-α. MK-886 significantly inhibited LT and enhanced PGE2 production in hypothalamus compared with LPS alone. These results suggest that 1) LPS-induced hypothermia may be mediated by LTs and 2) the antihypothermic effect of MK-886 is not associated with TNF-α bioactivity.

Human aging is associated with altered TNF-α production during hyperglycemia and hyperinsulinemia

2001 ◽  
Vol 281 (6) ◽  
pp. E1137-E1143 ◽  
Author(s):  
John P. Kirwan ◽  
Raj K. Krishnan ◽  
James A. Weaver ◽  
Luis F. Del Aguila ◽  
William J. Evans
Keyword(s):  
Glucose Metabolism ◽  
Insulin Action ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Normal Glucose Tolerance ◽  
Peripheral Blood Mononuclear ◽  
Significant Group ◽  
Hyperglycemic Clamp ◽  
Tnf Α ◽  
Factor Α

Changes in tumor necrosis factor-α (TNF-α) may provide a mechanism to explain impaired glucose metabolism with advancing age. Hyperglycemic clamps (180 min, 10 mM) were performed on seven older [67 ± 2 yr; body mass index (BMI) 24.7 ± 1.0 kg/m2] and seven younger (22 ± 1 yr; BMI 21.8 ± 1.3 kg/m2) healthy sedentary males with normal glucose tolerance. TNF-α production at basal and at the end of 180 min of hyperglycemia and hyperinsulinemia was measured ex vivo from lipopolysaccharide-stimulated (1 ng/ml) peripheral blood mononuclear cells. Plasma glucose, insulin, and C-peptide levels were similar in both groups at basal and during the last 30 min of the hyperglycemic clamp. Glucose infusion rates were lower ( P < 0.004) in the older group compared with the young, indicating decreased insulin action among the older subjects. Basal TNF-α secretion was similar in older and younger subjects. TNF-α was suppressed ( P < 0.02) in the younger group (230 ± 46 vs. 126 ± 49 pg/ml; basal vs. clamp) but not in the older group (153 ± 37 vs. 182 ± 42 pg/ml), with significant group differences in response ( P < 0.05). A significant correlation was observed between the level of suppression in TNF-α production and insulin action (Kendall's rank, τ = 0.40, P < 0.05). Furthermore, the TNF-α response during the clamp was related to fat mass ( r = 0.88, P < 0.001) and abdominal fat ( r = 0.81, P < 0.003). In conclusion, these findings suggest a possible mechanism by which TNF-α may modulate glucose metabolism in younger people. Aging and modest increases in adiposity prevent the “normal” suppression of TNF-α production after a sustained postprandial-like hyperglycemic-hyperinsulinemic stimulus, which may contribute in part to the decline in insulin sensitivity in older men.

Differences in MSU-induced Superoxide Responses by Neutrophils from Gout Subjects Compared to Healthy Controls and a Role for Environmental Inflammatory Cytokines and Hyperuricemia in Neutrophil Function and Survival

2010 ◽  
Vol 37 (6) ◽  
pp. 1228-1235 ◽  
Author(s):  
WILLIAM JOHN MARTIN ◽  
REBECCA GRAINGER ◽  
ANDREW HARRISON ◽  
JACQUIE L. HARPER
Keyword(s):  
Neutralizing Antibodies ◽  
Ex Vivo ◽  
Elevated Serum ◽  
Neutrophil Function ◽  
Superoxide Production ◽  
Healthy Controls ◽  
Serum Samples ◽  
Tnf Α ◽  
Neutrophil Superoxide ◽  
Factor Α

Objective.To determine whether monosodium urate (MSU) crystal-induced superoxide production is greater for neutrophils from patients with gout compared to asymptomatic hyperuricemic and healthy controls, and whether neutrophil functions are altered by an MSU crystal-induced inflammatory environment.Methods.Neutrophils were purified from the whole blood of study participants, restimulated with 500 mg MSU crystalsex vivo, and superoxide production measured using the colorimetric dye WST-1. Purified neutrophils were exposed to conditioned media from MSU crystal-activated blood monocyte cultures with and without neutralizing antibodies for interleukin 1ß (IL-1ß), IL-8 (CXCL8), IL-6, and tumor necrosis factor-α (TNF-α). Neutrophil superoxide production was measured and neutrophil apoptosis and IL-8 production were determined by flow cytometry. Serum samples were collected from participants and analyzed by Lincoplex bead array for IL-1ß, IL-8, IL-6, and TNF-α.Results.Neutrophils from gout and asymptomatic hyperuricemic subjects produced higher levels of MSU crystal-induced superoxide, and a weak trend toward elevated serum cytokines was observed compared to healthy controls. A correlation between serum uric acid and elevated neutrophil superoxide production was also observed. Neutrophils exposed to media from MSU crystal-activated monocytes exhibited enhanced superoxide production to MSU-crystal stimulation, increased IL-8 production, and extended cell survival that was predominantly dependent on IL-8, TNF-α and IL-6, respectively.Conclusion.Neutrophils from gout and asymptomatic hyperuricemic individuals are primed for enhanced MSU crystal-induced superoxide production that may be driven by a subclinical inflammatory cytokine environment combined with hyperuricemia. This inflammatory environment likely contributes to elevated neutrophil IL-8 production and survival in the absence of direct crystal stimulation. Asymptomatic hyperuricemia is not associated with suppressed neutrophil function.

scholarly journals TNF-α increases sensitivity to LPS in chronically catheterized rats

2001 ◽  
Vol 280 (6) ◽  
pp. H2857-H2862 ◽  
Author(s):  
Masakatsu Goto ◽  
Lucy V. Deriy ◽  
Yong J. Chen ◽  
David W. A. Beno ◽  
Michael R. Uhing ◽  
...  
Keyword(s):  
Blood Lactate ◽  
Severe Trauma ◽  
Interferon Γ ◽  
Bacterial Toxins ◽  
Peak Serum ◽  
Serum Concentrations ◽  
Tnf Α ◽  
Subsequent Exposure ◽  
Ifn Γ ◽  
Factor Α

Patients with severe trauma injury are transiently exposed to increased serum concentrations of tumor necrosis factor-α (TNF-α). These patients are susceptible to the development of multisystem organ failure (MSOF) triggered by subsequent exposure to bacterial toxins either via infection or increased intestinal permeability. We simulated the cytokine response of trauma by infusing 0.8 or 8.0 μg/kg of TNF-α (priming dose) into chronically catheterized rats. After 48 h, rats were challenged with endotoxin [lipopolysaccharide (LPS); 10 or 1,000 μg/kg]. Animals primed with either dose of TNF-α and then challenged with 1,000 μg/kg of LPS demonstrated significantly increased mortality, mean peak serum concentrations of interferon-γ (IFN-γ), and blood lactate concentrations ( P < 0.05) compared with nonprimed animals. Mean peak serum concentrations of IFN-γ and blood lactate concentrations were increased after challenge with 10 μg/kg of LPS only in animals primed with 8.0 μg/kg of TNF-α. Priming with TNF-α did not increase mortality after challenge with 10 μg/kg of LPS. These data suggest that both TNF-α release and the subsequent exposure to bacterial toxins mediate the pathophysiological progression from trauma to subsequent MSOF.

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