scholarly journals Cytokine patterns in a comparative model of arenavirus haemorrhagic fever in guinea pigs

2008 ◽  
Vol 89 (10) ◽  
pp. 2569-2579 ◽  
Author(s):  
Erin P. Scott ◽  
Judith F. Aronson
Keyword(s):  
Innate Immunity ◽  
Inflammatory Responses ◽  
Febrile Illness ◽  
Target Cells ◽  
Lassa Virus ◽  
Mrna Levels ◽  
Haemorrhagic Fever ◽  
Blood Leukocytes ◽  
Necrosis Factor Alpha ◽  
Monocyte Chemoattractant Protein 1

Arenaviruses such as Lassa virus cause a spectrum of disease in humans ranging from mild febrile illness to lethal haemorrhagic fever. The contributions of innate immunity to protection or pathogenicity are unknown. We compared patterns of expression of cytokines of innate immunity in mild versus severe arenavirus disease using an established guinea pig model based on the macrophage-tropic arenavirus Pichinde virus (PICV). Cytokine transcripts were measured by using real-time RT-PCR in target organs and blood during mild infection (caused by PICV, P2 variant) and lethal haemorrhagic fever (caused by PICV, P18 variant). In the initial peritoneal target cells, virulent P18 infection was associated with significantly increased gamma interferon (IFN-γ) and monocyte chemoattractant protein-1 (MCP-1, CCL2) mRNA levels relative to P2 infection. Peritoneal cells from P18-infected animals had decreased tumour necrosis factor alpha (TNF-α), interleukin (IL)-8 (CXCL-8) and IL-12p40 transcripts relative to mock-infected animals. Late in infection, P18-infected peripheral blood leukocytes (PBL) had decreased TNF-α, IFN-γ, and regulated upon activation, normal T cell expressed and secreted (RANTES, CCL-5) cytokine transcripts relative to P2-infected PBL. We conclude that, in severe arenavirus disease, patterns of cytokine expression in the initially infected cells favour recruitment of additional target monocytes, while inhibiting some of their pro-inflammatory responses. Suppression rather than overexpression of pro-inflammatory cytokines accompanied the terminal shock in this model of arenavirus haemorrhagic fever.

scholarly journals Lysine demethylase 1A exacerbates LPS-induced inflammation of vascular smooth muscle cells through modulation of NF-κB activation

2020 ◽  
Vol 19 (3) ◽  
pp. 481-487
Author(s):  
Ling Liang ◽  
Mingliang Sun ◽  
Zhongquan Qi ◽  
Weihua Li
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Inflammatory Responses ◽  
Muscle Cells ◽  
Mrna Levels ◽  
Small Interfering Rnas ◽  
Monocyte Chemoattractant Protein 1 ◽  
Lysine Demethylase

Purpose: To study the effect of lysine demethylase 1A (LSD1) on inflammatory responses of vascular smooth muscle cells (VSMCs), and investigate the mechanism. Methods: VSMCs were treated with lipopolysaccharide (LPS). Overexpression and knockdown of LSD1 in VSMCs were performed by transfecting with LSD1 overexpression plasmid and small interfering RNAs (siRNAs), respectively. Western blot and quantitative real-time polymerase chain reaction (qRTPCR) were used to measure protein and mRNA levels. Enzyme-linked immunosorbent (ELISA) assay was used to determine the levels of inflammatory cytokines. Results: Phosphorylation of LSD1 (p-LSD1) was significantly increased in LPS-induced VSMCs. Monocyte chemoattractant protein-1 and IL-6 levels were also increased by LPS, but attenuated by LSD1 knockdown in VSMCs. Activation of NF-κB was increased by LPS, but was also decreased by LSD1 knockdown. Level of methylated p65 (p65-me) in VSMCs was increased by treatment with SET7/9 (p65 methyltransferase), but this effect was attenuated by overexpression of LSD1. Besides, the increased levels of MCP-1 and IL-6 induced by overexpression of LSD1 were reversed by NF-κB signaling inhibitor, PDTC. Conclusion: LSD1 exacerbates LPS-induced inflammation of VSMCs through NF-κB activation via p65 demethylation, which indicates that LSD1 might be a potential target for the treatment of cardiovascular diseases. Keywords: Vascular smooth muscle cells, Lysine demethylase 1A, Phosphorylation, NF-κB, p65, Demethylation

scholarly journals A microarray analysis of the murine macrophage response to infection with Francisella tularensis LVS

2006 ◽  
Vol 55 (8) ◽  
pp. 1023-1033 ◽  
Author(s):  
Henrik Andersson ◽  
Blanka Hartmanová ◽  
Patrik Rydén ◽  
Laila Noppa ◽  
Linda Näslund ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Francisella Tularensis ◽  
Inflammatory Responses ◽  
Target Cells ◽  
Necrosis Factor Alpha ◽  
Macrophage Response ◽  
Time Points ◽  
Infected Cells ◽  
Cytopathogenic Effect ◽  
Oxide Synthase

The response of cells of the mouse macrophage cell line J774 to infection with Francisella tularensis LVS was analysed by means of a DNA microarray representing approximately 18 500 genes (20 600 clones). The adaptive response was modest at all time points, and at most, 81 clones were differentially regulated from the time point of uptake of bacteria (0 min) up to 240 min later. For all five time points, 229 clones fulfilled the criteria of being differentially regulated, i.e. the ratio between infected versus non-infected cells was at least 1.7-fold up- or down-regulated and P <0.05. It was found that many of the differentially regulated genes are known to respond to stress in general and to oxidative stress specifically. However, at 120 min it was observed that genes that lead to depletion of glutathione were upregulated. Possibly, this was a result of mechanisms induced by F. tularensis. Generally, there was a conspicuous lack of inflammatory responses and, for example, although tumour necrosis factor alpha (TNF-α) was upregulated at 0 min, a significant down-regulation was noted at all subsequent time points. When cells were treated with an inhibitor of inducible nitric oxide synthase (iNOS) or the antioxidant N-acetylcysteine (NAC), the infection-induced cytopathogenic effect was significantly inhibited. Together, the results suggest that F. tularensis LVS infection confers an oxidative stress upon the target cells and that many of the host-defence mechanisms appear to be intended to counteract this stress. The infection is characterized by a very modest inflammatory response.

scholarly journals Molecular Characterization of the Acute Inflammatory Response to Infections with Gram-Negative versus Gram-Positive Bacteria

2003 ◽  
Vol 71 (10) ◽  
pp. 5803-5813 ◽  
Author(s):  
Robert J. Feezor ◽  
Caroline Oberholzer ◽  
Henry V. Baker ◽  
Daniela Novick ◽  
Menachem Rubinstein ◽  
...  
Keyword(s):  
Whole Blood ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Interleukin 1 ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Blood Leukocytes ◽  
Necrosis Factor Alpha ◽  
Gram Negative ◽  
Gram Positive Bacteria

ABSTRACT Sepsis caused by gram-negative bacteria and that caused by gram-positive bacteria often manifest similar clinical features. We investigated plasma proinflammatory cytokine profiles in patients with sepsis due to gram-positive and gram-negative bacteria and studied the cytokine production and differential gene regulation of leukocytes stimulated ex vivo with Escherichia coli lipopolysaccharide or heat-killed Staphylococcus aureus. Concentrations of tumor necrosis factor alpha, interleukin 1 receptor antagonist (IL-1Ra), IL-8, IL-10, IL-18 binding protein, procalcitonin, and protein C in plasma did not differ between patients with sepsis due to gram-negative and gram-positive bacteria. However, plasma IL-1β, IL-6, and IL-18 concentrations were significantly higher in patients with sepsis due to gram-positive bacteria. Ex vivo stimulation of whole blood with heat-killed S. aureus markedly increased IL-1β and IL-18 levels more than E. coli lipopolysaccharide stimulation. Microarray analysis revealed at least 359 cross-validated probe sets (genes) significant at the P < 0.001 level whose expression discriminated among gram-negative-organism-stimulated, gram-positive-organism-stimulated, and unstimulated whole-blood leukocytes. The host inflammatory responses to gram-negative and gram-positive stimuli share some common response elements but also exhibit distinct patterns of cytokine appearance and leukocyte gene expression.

scholarly journals Chromatin-Specific Remodeling by HMGB1 and Linker Histone H1 Silences Proinflammatory Genes during Endotoxin Tolerance

2009 ◽  
Vol 29 (7) ◽  
pp. 1959-1971 ◽  
Author(s):  
Mohamed El Gazzar ◽  
Barbara K. Yoza ◽  
Xiaoping Chen ◽  
Benjamin A. Garcia ◽  
Nicolas L. Young ◽  
...  
Keyword(s):  
High Mobility ◽  
Histone H1 ◽  
Linker Histone ◽  
Mrna Levels ◽  
Transcription Activator ◽  
Blood Leukocytes ◽  
Necrosis Factor Alpha ◽  
Linker Histone H1 ◽  
Tnf Α ◽  
H3k9 Dimethylation

ABSTRACT Epigenetic silencing of tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) transcription occurs in blood leukocytes of animals and humans after the initiation of severe systemic inflammation (SSI). We previously reported that the epigenetic signature requires induction of NF-κB factor RelB, which directs histone H3K9 dimethylation, disrupts assembly of transcription activator NF-κB p65, and induces a sustained switch from the euchromatin to heterochromatin. Here, we report the novel findings that intracellular high mobility group box 1 protein (HMGB1) and nucleosome linker histone H1 protein are necessary components of endotoxin-mediated silencing of TNF-α in THP-1 human promonocytes. HMGB1 binds the TNF-α promoter during transcription silencing and promotes assembly of the repressor RelB. Depletion of HMGB1 by small interfering RNA results in dissociation of RelB from the promoter and partially restores TNF-α transcription. Histone H1, which typically displaces HMGB1 from nucleosomal DNA, also binds concomitantly with HMGB1 to the heterochromatin of the silenced TNF-α promoter. Combined knockdown of HMGB1 and H1 restores binding of the transcriptionally active NF-κB p65 and reestablishes TNF-α mRNA levels. Chromatin reimmunoprecipitation experiments demonstrate that HMGB1 and H1 are likely recruited to TNF-α sequences independently and that their binding correlates with histone H3K9 dimethylation, as inhibition of histone methylation blocks HMGB1 and H1 binding. Moreover, HMGB1- and H1-mediated chromatin modifications are gene specific during endotoxin silencing in that they also bind and repress acute proinflammatory IL-1β, while no binding nor repression of antiinflammatory IκBα is observed. Finally, we find that H1 and HMGB1 bind to the TNF-α a promoter in human leukocytes obtained from patients with SSI. We conclude proinflammatory HMGB1 and structural nucleosome linker H1 couple as a component of the epigenetic complex that silences acute proinflammatory TNF-α during the assembly of heterochromatin in the SSI phenotype.

Respiratory syncytial virus upregulates expression of the substance P receptor in rat lungs

1999 ◽  
Vol 277 (4) ◽  
pp. L831-L840 ◽  
Author(s):  
Giovanni Piedimonte ◽  
Maria M. Rodriguez ◽  
Katherine A. King ◽  
Stafford McLean ◽  
Xiaobo Jiang
Keyword(s):  
Respiratory Syncytial Virus ◽  
Substance P ◽  
Inflammatory Responses ◽  
Receptor Gene ◽  
Neutral Endopeptidase ◽  
Sensory Nerves ◽  
Respiratory Pathogen ◽  
Target Cells ◽  
Mrna Levels ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) is a major respiratory pathogen in infants. The first goal of this study was to determine whether the infection following endotracheal inoculation of RSV in Fischer 344 rats results in increased inflammatory responses to substance P (SP) either released by capsaicin from sensory nerves or injected into the circulation. Five days after inoculation, the extravasation of Evans blue-labeled albumin after capsaicin or SP was significantly greater in RSV-infected airways than in pathogen-free controls. The peptide-degrading activity of the regulatory enzyme neutral endopeptidase was unaffected by RSV. However, SP(NK1) receptor mRNA levels increased fivefold in RSV-infected lungs, and the density of SP binding sites in the bronchial mucosa increased threefold. These data suggest that RSV makes the airways abnormally susceptible to the proinflammatory effects of SP by upregulating SP(NK1) receptor gene expression, thereby increasing the density of these receptors on target cells. This effect may contribute to the inflammatory reaction to the virus and could be a target for the therapy of RSV disease and its sequelae.

scholarly journals The 5,7-Dimethoxyflavone Suppresses Sarcopenia by Regulating Protein Turnover and Mitochondria Biogenesis-Related Pathways

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1079 ◽  
Author(s):  
Changhee Kim ◽  
Jae-Kwan Hwang
Keyword(s):  
Muscle Mass ◽  
Protein Turnover ◽  
Inflammatory Responses ◽  
Biological Activities ◽  
Muscle Disease ◽  
Initiation Factor ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Necrosis Factor Alpha ◽  
Peroxisome Proliferator Activated Receptor

Sarcopenia is a muscle disease featured by the loss of muscle mass and dysfunction with advancing age. The 5,7-dimethoxyflavone (DMF), a major flavone found in Kaempferia parviflora, has biological activities, including anti-diabetes, anti-obesity, and anti-inflammation. However, its anti-sarcopenic effect remains to be elucidated. This current study investigated the inhibitory activity of DMF on sarcopenia. Eighteen-month-old mice were orally administered DMF at the dose of 25 mg·kg−1·day−1 or 50 mg·kg−1·day−1 for 8 weeks. DMF not only stimulated grip strength and exercise endurance but also increased muscle mass and volume. Besides, DMF stimulated the phosphatidylinositol 3-kinase-Akt pathway, consequently activating the mammalian target of rapamycin-eukaryotic initiation factor 4E-binding protein 1-70-kDa ribosomal protein S6 kinase pathway for protein synthesis. DMF reduced the mRNA expression of E3 ubiquitin ligase- and autophagy-lysosomal-related genes involved in proteolysis via the phosphorylation of Forkhead box O3. DMF upregulated peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, nuclear respiratory factor 1, and mitochondrial transcription factor A along with the increase of relative mitochondrial DNA content. DMF alleviated inflammatory responses by reducing the tumor necrosis factor-alpha and interleukin-6 serum and mRNA levels. Collectively, DMF can be used as a natural agent to inhibit sarcopenia via improving protein turnover and mitochondria function.

scholarly journals Differences in Cytokine Gene Expression after a Stimulation with Escherichia Coli and Porphyromonas Gingivalis or Lipopolysaccharides Derived from these Bacteria

2020 ◽  
Vol 7 (1) ◽  
pp. 13-20
Author(s):  
Nobuyasu Yukimasa ◽  
Yuna Kanaoka ◽  
Misaki Okito ◽  
Wataru Oboshi ◽  
Shoichi Sato ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Inflammatory Responses ◽  
Early Stage ◽  
Expression Profiles ◽  
Bacterial Species ◽  
Cytokine Gene Expression ◽  
Bacterial Antigen ◽  
Mrna Levels ◽  
Cytokine Gene ◽  
E Coli

Monocytes are important cells in innate immunity. The early stage of the innate immunity is regulated by various cytokines produced by monocytes. We conducted a preliminary study to investigate TNFα expression by stimulating THP-1 cells with several bacterial species. The TNFα mRNA levels significantly varied, with the most potent stimulatory effects observed with P. gingivalis. In the present study, we focused on P. gingivalis and compared differences in cytokine expression profiles after the stimulation of THP-1 with E. coli. Bacterial antigen stimulation increased various cytokine gene expressions in THP-1. P. gingivalis had significantly more potent effects on the mRNA expressions of TNFα, IL-1β, and IL-10, but not of IL-12p40, than E. coli. This result suggests the potent ability of P. gingivalis to induce inflammation. THP-1 stimulated with LPS derived from both bacterial species showed that E. coli had significantly more potent effects on the expressions of TNFα, IL-1β, and IL-12p40 than P. gingivalis. The differences in the bacterial antigens and the LPS stimulation effects suggest involvements of different receptors, such as TLR-2 and -4, which recognize bacterial components. The present results suggest that the P. gingivalis somatic cell antigen stimulates a number of pattern recognition receptors at the same time as the synthesis of bacterial components, except LPS. The potent virulence of P. gingivalis and persistence of infection might be affected by differences in cytokine production. Pro-inflammatory responses are dependent not only on the bacterial type, but also bacterial components.

scholarly journals Analysis of an association of TNF –308G>A polymorphism with a risk for pulmonary sarcoidosis in the Russian population of the Republic of Karelia

2017 ◽  
Vol 89 (3) ◽  
pp. 61-64
Author(s):  
I E Malysheva ◽  
L V Topchieva ◽  
E L Tikhonovich ◽  
O Yu Barysheva
Keyword(s):  
Peripheral Blood ◽  
Inflammatory Responses ◽  
Clinical Manifestations ◽  
Pulmonary Sarcoidosis ◽  
Russian Population ◽  
Control Group ◽  
Mrna Levels ◽  
Peripheral Blood Leukocytes ◽  
Blood Leukocytes ◽  
The Republic

Aim. To analyze an association of TNF –308G>A polymorphism with a risk for pulmonary sarcoidosis (PS) in the Russian population of the Republic of Karelia Subjects and methods. 84 patients with persistent PS and 96 donors without clinical manifestations of this disease (a control group) were examined. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was used to identify alleles and genotypes by the marker of TNF –308G>A polymorphism. The level of transcripts of the above gene in the peripheral blood leukocytes of healthy and sick people was determined by real-time PCR. Results. There were no significant differences in the distribution of allelic and genotypic frequencies by the marker of TNF –308G>A polymorphism between the control and PS patient groups. There was a significant increase in the number of TNF gene transcripts in the peripheral blood leukocytes of patients with PS compared to the controls. At the same time, there were no marked differences in mRNA expression levels in the above gene in the carriers of different genotypes by the marker of TNF –308G>A polymorphism in all the examined groups. Conclusion. The marker of TNF –308G>A polymorphism is unassociated with the risk of PS in the Russian population of the Republic of Karelia. No differences in TNF mRNA levels in the carriers of different genotypes by the above marker may suggest that the found elevated level of transcripts in the above gene in patients with diagnosed with PS is due to the development of the body’s inflammatory responses in this disease.

scholarly journals Coxsackievirus A2 Leads to Heart Injury in a Neonatal Mouse Model

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1588
Author(s):  
Wangquan Ji ◽  
Peiyu Zhu ◽  
Ruonan Liang ◽  
Liang Zhang ◽  
Yu Zhang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Inflammatory Responses ◽  
Tissue Growth ◽  
Neonatal Mouse ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Signal Pathways ◽  
Necrosis Factor Alpha ◽  
Monocyte Chemoattractant Protein 1 ◽  
Expression Levels ◽  
Heart Injury

Coxsackievirus A2 (CVA2) has emerged as an active pathogen that has been implicated in hand, foot, and mouth disease (HFMD) and herpangina outbreaks worldwide. It has been reported that severe cases with CVA2 infection develop into heart injury, which may be one of the causes of death. However, the mechanisms of CVA2-induced heart injury have not been well understood. In this study, we used a neonatal mouse model of CVA2 to investigate the possible mechanisms of heart injury. We detected CVA2 replication and apoptosis in heart tissues from infected mice. The activity of total aspartate transaminase (AST) and lactate dehydrogenase (LDH) was notably increased in heart tissues from infected mice. CVA2 infection also led to the disruption of cell-matrix interactions in heart tissues, including the increases of matrix metalloproteinase (MMP)3, MMP8, MMP9, connective tissue growth factor (CTGF) and tissue inhibitors of metalloproteinases (TIMP)4. Infiltrating leukocytes (CD45+ and CD11b+ cells) were observed in heart tissues of infected mice. Correspondingly, the expression levels of inflammatory cytokines in tissue lysates of hearts, including tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), IL6 and monocyte chemoattractant protein-1 (MCP-1) were significantly elevated in CVA2 infected mice. Inflammatory signal pathways in heart tissues, including phosphatidylinositol 3-kinase (PI3K)-AKT, mitogen-activated protein kinases (MAPK) and nuclear factor kappa B (NF-κB), were also activated after infection. In summary, CVA2 infection leads to heart injury in a neonatal mouse model, which might be related to viral replication, increased expression levels of MMP-related enzymes and excessive inflammatory responses.

Babesia bovis:lipids from virulent S2P and attenuated R1A strains trigger differential signalling and inflammatory responses in bovine macrophages

Parasitology ◽  
2013 ◽  
Vol 140 (4) ◽  
pp. 530-540 ◽  
Author(s):  
G. GIMENEZ ◽  
M. L. BELAUNZARÁN ◽  
C. V. PONCINI ◽  
F. C. BLANCO ◽  
I. ECHAIDE ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Significant Inhibition ◽  
Babesia Bovis ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
Adult Cattle ◽  
Mrna Induction ◽  
Lipid Fractions

SUMMARYThe intra-erythrocytic protozoanBabesia bovisis an economically important pathogen that causes an acute and often fatal infection in adult cattle. Babesiosis limitation depends on the early activation of macrophages, essential cells of the host innate immunity, which can generate an inflammatory response mediated by cytokines and nitric oxide (NO). Herein, we demonstrate in bovine macrophages that lipids fromB. bovisattenuated R1A strain (LA) produced a stronger NO release, an early TNFαmRNA induction and 2-fold higher IL-12p35 mRNA levels compared to the lipids of virulent S2P strain (LV). Neither LAnor LVinduced anti-inflammatory IL-10. Regarding signalling pathways, we here report that LAinduced a significant phosphorylation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) whereas LVonly induced a reduced activation of ERK1/2. Besides, NF-κB was activated by LAand LV, but LAproduced an early degradation of the inhibitor IκB. Interestingly, LVand the majority of its lipid fractions, exerted a significant inhibition of concanavalin A-induced peripheral blood mononuclear cell proliferation with respect to LAand its corresponding lipid fractions. In addition, we determined that animals infected with R1A developed a higher increase in IgM anti-phosphatidylcholine than those inoculated with S2P. Collectively, S2P lipids generated a decreased inflammatory response contributing to the evasion of innate immunity. Moreover, since R1A lipids induced a pro-inflammatory profile, we propose these molecules as good candidates for immunoprophylactic strategies against babesiosis.

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