scholarly journals Immune Suppression Induced by Gallibacterium anatis GtxA During Interaction with Chicken Macrophage-Like HD11 Cells

Toxins ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 536
Author(s):  
Bo Tang ◽  
Anders M. Bojesen
Keyword(s):  
Cell Death ◽  
Bacterial Strains ◽  
Rt Pcr ◽  
Spleen Tissue ◽  
Host Cell Response ◽  
Tnf Α ◽  
Chicken Macrophage ◽  
Adhesion And Invasion ◽  
Invasion Assays

The RTX toxin GtxA expressed by Gallibacterium anatis biovar haemolytica has been proposed a major virulence factor during disease manifestations in the natural host, the chicken. To better understand the role of GtxA in the pathogenesis of G. anatis, we compared the GtxA expressing wildtype strain with its isogenic ∆gtxA mutant that was unable to express GtxA during exposure to chicken macrophage-like HD11 cells. From adhesion and invasion assays, we showed that GtxA appears to promote adhesion and invasion of HD11 cells. By using quantitative RT-PCR, we also demonstrated that the G. anatis expressing GtxA induced a mainly anti-inflammatory (IL-10) host cell response as opposed to the pro-inflammatory (IL-1β, IL-6 and TNF-α) response induced by the GtxA deletion mutant. Interestingly, these results, at least partly, resemble recent responses observed from spleen tissue of chickens infected with the same two bacterial strains. The effect of the GtxA toxin on the type of cell death was less clear. While GtxA clearly induced cell death, our efforts to characterize whether this was due to primarily necrosis or apoptosis through expression analysis of a broad range of apoptosis genes did not reveal clear answers.

Abstract 507: Activation of the Classically Pro-Apoptotic Death Receptor 5 Promotes Physiological Hypertrophy and Cardiomyocyte Survival

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Toby Thomas ◽  
Miles Tanner ◽  
Laurel Grisanti
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Cardiac Fibrosis ◽  
Death Receptor ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Death Receptor 5 ◽  
Tnf Α ◽  
Cardiomyocyte Survival

Heart failure is hallmarked by a combination of cardiomyocyte hypertrophy and death. Apoptosis, one of the primary mechanisms of cell death, occurs through finely tuned extrinsic or intrinsic pathways. Of the mediators involved in extrinsic apoptotic signaling, some have been extensively studied, such as tumor necrosis factor ((TNF)-α), while others have been relatively untouched. One such receptor is Death Receptor 5 (DR5) which, along with its ligand TNF-Related Apoptosis Inducing Ligand (TRAIL), have recently been implicated as a biomarker in determining the progression and outcome in patients following multiple heart failure etiologies, suggesting a novel role of DR5 signaling in the heart. These studies suggest a potentially protective role for DR5 in the heart; however, the function of TRAIL/DR5 in the heart has been virtually unstudied. Our goal was to explore the role of TRAIL/DR5 in cardiomyocyte hypertrophy and survival with the hypothesis that DR5 promotes cardiomyocyte survival and growth through non-canonical mechanisms. Mice treated with the DR5 agonist bioymifi or a DR5 agonist antibody, MD5-1, were absent of cell death, while an increase in hypertrophy was observed without a decline in cardiac function. In isolated cardiomyocytes, this pro-hypertrophic phenotype was determined to operate through MMP-dependent cleavage of HB-EGFR, leading to transactivation of EGFR and ERK1/2 signaling. To determine the role of DR5 in heart failure, a chronic catecholamine administration model was used and DR5 activation was found to decrease cardiomyocyte death and cardiac fibrosis. ERK1/2, a well characterized pro-survival, pro-hypertrophic kinase is activated in the heart with DR5 agonist administration and may represent the mechanistic link through which DR5 is imparting cardioprotection. In summary, DR5 activation promotes cardiomyocyte hypertrophy and survival and prevents cardiac fibrosis via a non-canonical MMP-EGFR-ERK1/2 pathway. Taken together, these studies identify a previously undetermined role for DR5 in the heart and identify novel therapeutic target for the treatment of heart failure.

scholarly journals A20: a master regulator of arthritis

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Yongyao Wu ◽  
Xiaomin He ◽  
Ning Huang ◽  
Jiayun Yu ◽  
Bin Shao
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Mouse Models ◽  
Inflammatory Arthritis ◽  
Molecular Mechanisms ◽  
Related Research ◽  
Inflammatory Protein ◽  
New Findings ◽  
Tnf Α

Abstract A20, also known as TNF-α-induced protein 3 (TNFAIP3), is an anti-inflammatory protein that plays an important part in both immune responses and cell death. Impaired A20 function is associated with several human inflammatory and autoimmune diseases. Although the role of A20 in mediating inflammation has been frequently discussed, its intrinsic link to arthritis awaits further explanation. Here, we review new findings that further demonstrate the molecular mechanisms through which A20 regulates inflammatory arthritis, and we discuss the regulation of A20 by many factors. We conclude by reviewing the latest A20-associated mouse models that have been applied in related research because they reflect the characteristics of arthritis, the study of which will hopefully cast new light on anti-arthritis treatments.

scholarly journals Calpains mediate acute renal cell death: role of autolysis and translocation

2001 ◽  
Vol 281 (4) ◽  
pp. F728-F738 ◽  
Author(s):  
Xiuli Liu ◽  
Juanita J. Rainey ◽  
Jay F. Harriman ◽  
Rick G. Schnellmann
Keyword(s):  
Cell Death ◽  
Mitochondrial Function ◽  
Immunoblot Analysis ◽  
Calpain Inhibitor ◽  
Antimycin A ◽  
Rt Pcr ◽  
Plasma Membrane Permeability ◽  
Injury Death ◽  
Casein Zymography

The goals of this study were to determine 1) the expression of calpain isoforms in rabbit renal proximal tubules (RPT); 2) calpain autolysis and translocation, and calpastatin levels during RPT injury; and 3) the effect of a calpain inhibitor (PD-150606) on calpain levels, mitochondrial function, and ion transport during RPT injury. RT-PCR, immunoblot analysis, and FITC-casein zymography demonstrated the presence of only μ- and m-calpains in rabbit RPT. The mitochondrial inhibitor antimycin A decreased RPT μ- and m-calpain and calpastatin levels in conjunction with cell death and increased plasma membrane permeability. No increases in either μ- or m-calpain were observed in the membrane nor were increases observed in autolytic forms of either μ- or m-calpain in antimycin A-exposed RPT. PD-150606 blocked antimycin A-induced cell death, preserved calpain levels in antimycin A-exposed RPT, and promoted the recovery of mitochondrial function and active Na+ transport in RPT after hypoxia and reoxygenation. The present study suggests that calpains mediate RPT injury without undergoing autolysis or translocation, and ultimately they leak from cells subsequent to RPT injury/death. Furthermore, PD-150606 allows functional recovery after injury.

TNF-α mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling

2005 ◽  
Vol 288 (2) ◽  
pp. F406-F411 ◽  
Author(s):  
R. Misseri ◽  
D. R. Meldrum ◽  
C. A. Dinarello ◽  
P. Dagher ◽  
K. L. Hile ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Apoptosis ◽  
Renal Cell ◽  
Fas Ligand ◽  
Tubular Cell ◽  
Caspase 8 ◽  
Renal Tubular Cell ◽  
Rt Pcr ◽  
Tnf Α ◽  
Renal Tubular

Obstruction of the upper urinary tract induces a progressive loss in renal mass through apoptotic renal cell death. Although TNF-α has been implicated in ischemia-reperfusion-induced apoptotic renal cell death, its role in obstructive renal cell apoptosis remains unknown. To study this, male Sprague-Dawley rats were subjected to left unilateral ureteral obstruction vs. sham operation. Twenty-four hours before surgery and every 84 h thereafter, rats received either vehicle or a pegylated form of soluble TNF receptor type 1 (PEG-sTNFR1). The kidneys were harvested 1, 3, or 7 days postoperatively, and tissue samples were subsequently analyzed for TNF-α (ELISA, RT-PCR), Fas ligand (RT-PCR), apoptosis (TUNEL, ELISA), and caspase 8 and 3 activity (Western blot). Renal obstruction induced increased tissue TNF-α and Fas ligand mRNA levels, TNF-α protein production, apoptotic renal tubular cell death, and elevated caspase 8 and 3 activity, whereas treatment with PEG-sTNFR1 significantly reduced obstruction-induced TNF-α production, renal tubular cell apoptosis, and caspase activity. PEG-sTNFR1 did not significantly alter Fas ligand expression. These results demonstrate that TNF-α mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling and identify TNF-α neutralization as a potential therapeutic option for the amelioration of obstruction-induced renal injury.

scholarly journals Role of Calcium in Pancreatic Islet Cell Death by IFN-γ/TNF-α

2004 ◽  
Vol 172 (11) ◽  
pp. 7008-7014 ◽  
Author(s):  
Inik Chang ◽  
Namjoo Cho ◽  
Sunshin Kim ◽  
Ja Young Kim ◽  
Eunshil Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Pancreatic Islet ◽  
Islet Cell ◽  
Pancreatic Islet Cell ◽  
Tnf Α ◽  
Ifn Γ

scholarly journals Neuron-Glia Crosstalk Plays a Major Role in the Neurotoxic Effects of Ketamine via Extracellular Vesicles

2021 ◽  
Vol 9 ◽  
Author(s):  
Donald H. Penning ◽  
Simona Cazacu ◽  
Aharon Brodie ◽  
Vesna Jevtovic-Todorovic ◽  
Steve N. Kalkanis ◽  
...  
Keyword(s):  
Cell Death ◽  
Extracellular Vesicles ◽  
Neuronal Cells ◽  
Neural Cells ◽  
General Anesthetics ◽  
Rt Pcr ◽  
Neurotoxic Effects ◽  
The Impact ◽  
Bdnf Pathway

Background: There is a compelling evidence from animal models that early exposure to clinically relevant general anesthetics (GAs) interferes with brain development, resulting in long-lasting cognitive impairments. Human studies have been inconclusive and are challenging due to numerous confounding factors. Here, we employed primary human neural cells to analyze ketamine neurotoxic effects focusing on the role of glial cells and their activation state. We also explored the roles of astrocyte-derived extracellular vesicles (EVs) and different components of the brain-derived neurotrophic factor (BDNF) pathway.Methods: Ketamine effects on cell death were analyzed using live/dead assay, caspase 3 activity and PARP-1 cleavage. Astrocytic and microglial cell differentiation was determined using RT-PCR, ELISA and phagocytosis assay. The impact of the neuron-glial cell interactions in the neurotoxic effects of ketamine was analyzed using transwell cultures. In addition, the role of isolated and secreted EVs in this cross-talk were studied. The expression and function of different components of the BDNF pathway were analyzed using ELISA, RT-PCR and gene silencing.Results: Ketamine induced neuronal and oligodendrocytic cell apoptosis and promoted pro-inflammatory astrocyte (A1) and microglia (M1) phenotypes. Astrocytes and microglia enhanced the neurotoxic effects of ketamine on neuronal cells, whereas neurons increased oligodendrocyte cell death. Ketamine modulated different components in the BDNF pathway: decreasing BDNF secretion in neurons and astrocytes while increasing the expression of p75 in neurons and that of BDNF-AS and pro-BDNF secretion in both neurons and astrocytes. We demonstrated an important role of EVs secreted by ketamine-treated astrocytes in neuronal cell death and a role for EV-associated BDNF-AS in this effect.Conclusions: Ketamine exerted a neurotoxic effect on neural cells by impacting both neuronal and non-neuronal cells. The BDNF pathway and astrocyte-derived EVs represent important mediators of ketamine effects. These results contribute to a better understanding of ketamine neurotoxic effects in humans and to the development of potential approaches to decrease its neurodevelopmental impact.

scholarly journals Non-invasive Biomarkers of Liver Inflammation and Cell Death in Response to Alcohol Detoxification

2021 ◽  
Vol 12 ◽  
Author(s):  
Manuela G. Neuman ◽  
Johannes Mueller ◽  
Sebastian Mueller
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Growth Factor ◽  
Alcohol Withdrawal ◽  
Molecular Mechanisms ◽  
Non Invasive ◽  
Tnf Α ◽  
Heavy Drinkers ◽  
Alcohol Detoxification

IntroductionAlcohol-related liver disease (ALD) represents the most common liver disease worldwide, however, the underlying molecular mechanisms are still poorly understood. Namely centrilobular inflammation and programmed cell death are characteristic to ALD and it remains to be elucidated why they persist despite the absence of alcohol.AimsTo study the effects of alcohol withdrawal in a cohort of heavy drinkers and the role of cirrhosis by using non-invasive biomarkers such as cytokines, apoptotic and angiogenic markers.MethodsCaspase 3-cleaved M30, M65, cytokines (IL-6, IL-8), tumor necrosis factor alpha (TNF-α), transforming growth factor (TGF-β) and vascular endothelial growth factor (VEGF) were measured in 114 heavy drinkers. The role of alcohol detoxification was investigated in 45 patients. The liver histology was available in 23 patients. Fibrosis stage and steatosis were assessed by measuring liver stiffness (LS) and controlled attenuation parameter (CAP) in all patients using transient elastography (FibroScan, Echosens, Paris). Mean observation interval between the measurements was 5.7 ± 1.4 days (mean + –SD).ResultsPatients consumed a mean of 204 ± 148 g/day alcohol with a heavy drinking duration of 15.3 ± 11.0 years. Mean LS was 20.7 ± 24.4 kPa and mean CAP was 303 ± 51 dB/m. Fibrosis distribution was F0–38.1%, F1-2–31%, F3–7.1 and F4–23.9%. Apoptotic markers M30 and M65 were almost five times above normal. In contrast, TNF- α a, IL-8 and VEGF were only slightly elevated. Patients with manifest liver cirrhosis (F4) had significantly higher levels of M30, M65, IL-6 and IL-8. Histology features such as hepatocyte ballooning, Mallory-Denk bodies, inflammation and fibrosis were all significantly associated with elevated LS, and serum levels of TNF-alpha, M30 and M65 but not with CAP and other cytokines. During alcohol detoxification, LS, transaminases, TGF- β, IL-6, IL-8 and VEGF decreased significantly. In contrast, no significant changes were observed for M30, M65 and TNF- α and M30 even increased during detoxification in non-cirrhotic patients. Profibrogenic cytokine TGF-beta and pro-angiogenic cytokine VEGF showed a delayed decrease in patients with manifest cirrhosis.ConclusionPatients with alcohol-related cirrhosis have a pronounced apoptotic activity and a distinct inflammatory response that only partly improves after 1 week of alcohol detoxification. Alcohol withdrawal may represent an important approach to better dissect the underlying mechanisms in the setting of alcohol metabolism.

scholarly journals Internalization of Adenovirus by Alveolar Macrophages Initiates Early Proinflammatory Signaling during Acute Respiratory Tract Infection

2000 ◽  
Vol 74 (20) ◽  
pp. 9655-9667 ◽  
Author(s):  
Zsuzsanna Zsengellér ◽  
Kazuhisa Otake ◽  
Shaikh-Abu Hossain ◽  
Pierre-Yves Berclaz ◽  
Bruce C. Trapnell
Keyword(s):  
Tract Infection ◽  
Respiratory Tract ◽  
Alveolar Macrophages ◽  
Adenovirus Infection ◽  
Airway Epithelial ◽  
Rt Pcr ◽  
Inflammatory Signaling ◽  
Tnf Α

ABSTRACT Adenovirus is a common respiratory pathogen which causes a broad range of distinct clinical syndromes and has recently received attention for its potential for in vivo gene delivery. Although adenovirus respiratory tract infection (ARTI) results in dose-dependent, local inflammation, the pathogenesis of this remains unclear. We hypothesized that alveolar macrophages (AMφ) rapidly internalize adenovirus following in vivo pulmonary administration and then initiate inflammatory signaling within the lung. To evaluate the role of AMφ in the induction of lung inflammation during ARTI in vivo, we directly assessed adenovirus uptake by murine AMφ and correlated uptake with the initiation of proinflammatory gene expression. Stimulation of cytokine (tumor necrosis factor alpha [TNF-α], interleukin-6 [IL-6], macrophage inflammatory protein-2 [MIP-2], and MIP-1α) expression in the lung was evaluated at the level of mRNA (by reverse transcription-PCR [RT-PCR]) and protein (by enzyme-linked immunosorbent assay) and by identification of cells expressing TNF-α and IL-6 mRNA in lung tissues (by in situ hybridization) and isolated lung lavage cells (by RT-PCR). Adenovirus, labeled with the fluorescent dye (Cy3), was rapidly and widely distributed on epithelial surfaces of airways and alveoli and was very rapidly (∼1 min) localized within AMφ. At 30 min after infection AMφ but not airway epithelial or vascular endothelial cells expressed mRNA for TNF-α and IL-6, thus identifying AMφ as the cell source of initial cytokine signaling. IL-6, TNF-α, MIP-2, and MIP-1α levels progressively increased in bronchoalveolar lavage fluid after pulmonary adenovirus infection, and all were significantly elevated at 6 h (P < 0.05). To begin to define the molecular mechanism(s) by which adenovirus initiates the inflammatory signaling in macrophages, TNF-α expression from adenovirus-infected RAW264.7 macrophages was evaluated in vitro. TNF-α expression was readily detected in adenovirus-infected RAW cell supernatant with kinetics similar to AMφ during in vivo infection. Blockage of virus uptake at specific cellular sites, including internalization (by wortmannin), endosome acidification and/or lysis (by chloroquine) or by Ca2+ chelation (by BAPTA) completely blocked TNF-α expression. In conclusion, results showed that during ARTI, (i) AMφ rapidly internalized adenovirus, (ii) expression of inflammatory mediators was initiated within AMφ and not airway epithelial or other cells, and (iii) the initiation of inflammatory signaling was linked to virion uptake by macrophages occurring at a point after vesicle acidification. These results have implications for our understanding of the role of the AMφ in the initiation of inflammation following adenovirus infection and adenovirus-mediated gene transfer to the lung.

PD-L1 and PD-1 expressed in trigeminal ganglia may inhibit pain in an acute migraine model

Cephalalgia ◽  
2019 ◽  
Vol 40 (3) ◽  
pp. 288-298
Author(s):  
Suming Shi ◽  
Yuhang Han ◽  
Dan Wang ◽  
Ping Guo ◽  
Jiali Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Calcitonin Gene Related Peptide ◽  
Trigeminal Ganglia ◽  
Acute Migraine ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Tnf Α ◽  
Immunofluorescence Labeling

Background Neurogenic inflammation, mediated by the activation of primary neurons, is thought to be an important factor in migraine pathophysiology. Programmed cell death ligand-1 (PD-L1) can suppress the immune response through the Programmed cell death-1 receptor. However, the role of PD-L1/PD-1 in migraine remains unclear. In this study we evaluated the expression and role of PD-L1/PD-1 in the trigeminal ganglia in an animal model of acute migraine. Methods Acute nitroglycerin induces acute mechanical hyperalgesia that can be used as a readout of migraine-like pain. We investigated the expression of PD-L1 and PD-1 in the trigeminal ganglia in a mouse model by means of immunofluorescence labeling, quantitative reverse transcription-polymerase chain reaction and western blotting. We explored the effects of PD-1 in a migraine model by the von Frey test and by analyzing the expression of calcitonin gene-related peptide, interleukin-1β (IL-1β), interleukin-18 (IL-18), Tumor Necrosis Factor-α (TNF-α), interleukin-6 (IL-6) and transient receptor potential vanilloid (TRPV4) after the intravenous injection of a PD-1 inhibitor. Results PD-L1 and PD-1 immunoreactivity were present in healthy trigeminal ganglia neurons. The mRNA levels of PD-L1 and PD-1 were significantly elevated 2 h, 4 h and 6 h after acute nitroglycerin treatment ( p < 0.05). The protein levels of PD-L1 were significantly increased 2 h, 4 h and 6 h after treatment, and PD-1 was significantly increased at 2 h and 6 h. The blockade of PD-1 increased acute nitroglycerin-induced hyperalgesia, and this effect was accompanied by a more significant increase in calcitonin gene-related peptide, IL-1β, TNF-α, IL-6 and IL-18 in the trigeminal ganglia. Conclusion These findings suggest that PD-L1 and PD-1 might inhibit migraine-like pain by downregulating CGRP and inflammatory factors in the trigeminal ganglia. The use of PD-L1 and PD-1 as analgesics should be further studied.

scholarly journals Diphthamide Biosynthesis 1 is a Novel Oncogene in Colorectal Cancer Cells and is Regulated by MiR-218-5p

2017 ◽  
Vol 44 (2) ◽  
pp. 505-514 ◽  
Author(s):  
Minghui Liu ◽  
Kai Yin ◽  
Xu Guo ◽  
Huijin Feng ◽  
Min Yuan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Bioinformatics Analysis ◽  
Inverse Correlation ◽  
Luciferase Reporter ◽  
Pcr Analysis ◽  
Rt Pcr ◽  
Colorectal Cancer Cells ◽  
Invasion Assays

Background/Aims: This study focused on the oncogenic role of Diphthamide biosynthesis 1 (DPH1) in colorectal cancer (CRC) cells. Methods: The expression of DPH1 was determined by quantitative RT-PCR analysis and western blotting in CRC tissues. The role of DPH1 in CRC cells was investigated via cell viability and invasion assays under the condition of DPH1 silencing or overexpression. Bioinformatics analysis and luciferase reporter analysis were used to identify the upstream microRNA which might regulate DPH1.The inverse correlation between the microRNA and DPH1 was also detected in CRC cells. Results: We identified an unexpected role for DPH1 as an oncogene in CRC cells. The tumour-suppressive miR-218-5p regulates DPH1 directly and negatively. Loss of miR-218-5p drives the oncogenic role of DPH1 in CRC cells. Conclusion: The modulation of DPH1 by miR-218-5p may be an important regulatory axis during CRCtumourigenesis.

Sign in / Sign up

Export Citation Format

Share Document