scholarly journals Epinephrine Enhances the Response of Macrophages under LPS Stimulation

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Jianyun Zhou ◽  
Jun Yan ◽  
Huaping Liang ◽  
Jianxin Jiang
Keyword(s):  
Immune Responses ◽  
Underlying Mechanism ◽  
Phagocytic Index ◽  
Activated Macrophages ◽  
Sirna Interference ◽  
Lps Activation ◽  
Peak Value

Trauma associated with infection may directly trigger a neuroendocrine reactionin vivowhile the hormone epinephrine is known to mediate immune responses to inflammation after injury. However, the role of epinephrine during the earliest stage of trauma still remains unclear. We therefore explored the role of epinephrine on activated macrophages under LPS stimulationin vitroas well as the mechanisms underlying its effect. Dose- and time-dependent effects of epinephrine on macrophage immune function were assessed after LPS activation. We also employed CD14 siRNA interference to investigate whether CD14 played a role in the mechanism underlying the effect of epinephrine on LPS-induced macrophage responses. Our results showed that epinephrine pretreatment (10 ng/mL) significantly promoted immune responses from LPS stimulated macrophages, including phagocytic rate, phagocytic index, TNFα/IL-1β/IL-10 secretion, and CD14 expression (P< 0.05). Moreover, TNFα/IL-1β/IL-10 levels attained their peak value 1 hour after incubation with 10 ng/mL epinephrine (P< 0.05), and CD14 siRNA transfection dramatically decreased phagocytosis and cytokine secretion by LPS-activated macrophages (P< 0.05). We therefore conclude that 10 ng/mL epinephrine enhances immune responses from macrophages under LPS stimulation and that the underlying mechanism may relate to CD14 upregulation on the surface of macrophages.

scholarly journals New mutant mouse models clarify the role of NAIPs, phosphorylation, NLRP3, and tumors in NLRC4 inflammasome activation

2019 ◽  
Author(s):  
Jeannette L. Tenthorey ◽  
Roberto A. Chavez ◽  
Thornton W. Thompson ◽  
Katherine A. Deets ◽  
Russell E. Vance ◽  
...  
Keyword(s):  
Immune Responses ◽  
Mutant Mouse ◽  
Adaptor Protein ◽  
Underlying Mechanism ◽  
Inflammasome Activation ◽  
Biological Functions ◽  
Inflammasome Component

ABSTRACTThe NAIP/NLRC4 inflammasome is a cytosolic sensor of bacteria that activates Caspase-1 and initiates potent downstream immune responses. Structural, biochemical, and genetic data all demonstrate that the NAIP proteins act as receptors for specific bacterial ligands, while NLRC4 is a downstream adaptor protein that multimerizes with NAIPs to form a macromolecular structure called an inflammasome. However, several aspects of NLRC4 biology remain unresolved. For example, in addition to its clear function in responding to bacteria, NLRC4 has also been proposed to initiate anti-tumor responses, though the underlying mechanism is unknown. NLRC4 has also been shown to be phosphorylated on serine 533, and this modification was suggested to be important for NLRC4 function. In the absence of S533 phosphorylation, it was further proposed that another inflammasome component, NLRP3, can induce NLRC4 activation. We generated a new Nlrc4-deficient mouse line as well as mice encoding phosphomimetic S533D and non-phosphorylatable S533A NLRC4 proteins. Using these genetic models in vivo and in vitro, we fail to observe a role for phosphorylation in NLRC4 inflammasome function. Furthermore, we find no role for NLRP3 in NLRC4 function, or for NLRC4 in a model of melanoma. These results simplify and clarify our understanding of the mechanism of NAIP/NLRC4 activation and its biological functions.

scholarly journals Citrulline directly modulates muscle protein synthesis via the PI3K/MAPK/4E-BP1 pathway in a malnourished state: evidence from in vivo, ex vivo, and in vitro studies

2017 ◽  
Vol 312 (1) ◽  
pp. E27-E36 ◽  
Author(s):  
Servane Le Plénier ◽  
Arthur Goron ◽  
Athanassia Sotiropoulos ◽  
Eliane Archambault ◽  
Chantal Guihenneuc ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Ex Vivo ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Fold Increase ◽  
Underlying Mechanism ◽  
Muscle Homeostasis

Citrulline (CIT) is an endogenous amino acid produced by the intestine. Recent literature has consistently shown CIT to be an activator of muscle protein synthesis (MPS). However, the underlying mechanism is still unknown. Our working hypothesis was that CIT might regulate muscle homeostasis directly through the mTORC1/PI3K/MAPK pathways. Because CIT undergoes both interorgan and intraorgan trafficking and metabolism, we combined three approaches: in vivo, ex vivo, and in vitro. Using a model of malnourished aged rats, CIT supplementation activated the phosphorylation of S6K1 and 4E-BP1 in muscle. Interestingly, the increase in S6K1 phosphorylation was positively correlated ( P < 0.05) with plasma CIT concentration. In a model of isolated incubated skeletal muscle from malnourished rats, CIT enhanced MPS (from 30 to 80% CIT vs. Ctrl, P < 0.05), and the CIT effect was abolished in the presence of wortmannin, rapamycin, and PD-98059. In vitro, on myotubes in culture, CIT led to a 2.5-fold increase in S6K1 phosphorylation and a 1.5-fold increase in 4E-BP1 phosphorylation. Both rapamycin and PD-98059 inhibited the CIT effect on S6K1, whereas only LY-294002 inhibited the CIT effect on both S6K1 and 4E-BP1. These findings show that CIT is a signaling agent for muscle homeostasis, suggesting a new role of the intestine in muscle mass control.

scholarly journals Role of interleukin-1 and tumour necrosis factor in leukocyte recruitment to acute dermal inflammation

1992 ◽  
Vol 1 (5) ◽  
pp. 347-353 ◽  
Author(s):  
Andrew C. Issekutz ◽  
Nancy Lopes ◽  
Thomas B. Issekutz
Keyword(s):  
Monoclonal Antibody ◽  
Umbilical Vein ◽  
Interleukin 1 ◽  
E Coli ◽  
Tnf Α ◽  
Lps Activation ◽  
Necrosis Factor

The cytokines IL-1 and TNF-α are involved in inflammation and their production is stimulated by various agents, especially endotoxin (LPS). Here, using the human IL-1 receptor antagonist (IL-1RA) and a new monoclonal antibody (mAb 7F11) to rabbit TNF, the role of endogenous IL-l and TNF production in acute (3h) leukocyte (PMNL) recruitment to dermal inflammation in rabbits has been studied. IL-1RA inhibited by 27% the PMNL accumulation in reactions induced by killed Escherichia coli (p < 0.05) but not by LPS. The monoclonal antibody to TNF inhibited by 27% and 38% (p < 0.002) the PMNL accumulation in LPS and E. coli reactions respectively, but a combination of the mAb with IL-1RA was not more effective. Treatment of human umbilical vein endothelium with LPS for 3 h activated endothelium to induce PMNL transendothelial migration in vitro, which was not inhibited by IL-1RA, antibody to TNF-α, IL-1 or to IL-8. In conclusion, TNF and IL-1 may partially mediate acute PMNL infiltration in vivo to LPS and Gram negative bacteria, but there is a major IL-1/TNF independent mechanism, at least in dermal inflammation, which may be due to direct LPS activation of the microvasculature or perhaps the generation of cytokines other than IL-1 and TNF.

EDD1 predicts prognosis and regulates gastric cancer growth in vitro and in vivo via miR-22

2016 ◽  
Vol 0 (0) ◽  
Author(s):  
Min Yang ◽  
Nan Jiang ◽  
Qi-wei Cao ◽  
Qing Sun
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Patient Survival ◽  
Underlying Mechanism ◽  
Gastric Cancer Cells ◽  
Cancer Tissues

Abstract Gastric cancer is the most common digestive malignant tumor worldwild. EDD1 was reported to be frequently amplified in several tumors and played an important role in the tumorigenesis process. However, the biological role and potential mechanism of EDD1 in gastric cancer remains poorly understood. In this study, we are aim to investigate the effect of EDD1 on gastric cancer progression and to explore the underlying mechanism. The results showed the significant up-regulation of EDD1 in -gastric cancer cell tissues and lines. The expression level of EDD1 was also positively associated with advanced clinical stages and predicted poor overall patient survival and poor disease-free patient survival. Besides, EDD1 knockdown markedly inhibited cell viability, colony formation, and suppressed tumor growth. Opposite results were obtained in gastric cancer cells with EDD1 overexpression. EDD1 knockdown was also found to induce gastric cancer cells apoptosis. Further investigation indicated that the oncogenic role of EDD1 in regulating gastric cancer cells growth and apoptosis was related to its PABC domain and directly through targeting miR-22, which was significantly down-regulated in gastric cancer tissues. Totally, our study suggests that EDD1 plays an oncogenic role in gastric cancer and may be a potential therapeutic target for gastric cancer.

scholarly journals Role of Type I Interferons on Filovirus Pathogenesis

Vaccines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 22 ◽  
Author(s):  
Beatriz Escudero-Pérez ◽  
César Muñoz-Fontela
Keyword(s):  
Animal Models ◽  
Immune Responses ◽  
Marburg Virus ◽  
Type I Interferons ◽  
Type I ◽  
Adaptive Immune ◽  
Antigen Presenting

Filoviruses, such as Ebola and Marburg virus, encode viral proteins with the ability to counteract the type I interferon (IFN-I) response. These IFN-I antagonist proteins are crucial to ensure virus replication, prevent an antiviral state in infected and bystander cells, and impair the ability of antigen-presenting cells to initiate adaptive immune responses. However, in recent years, a number of studies have underscored the conflicting data between in vitro studies and in vivo data obtained in animal models and clinical studies during outbreaks. This review aims to summarize these data and to discuss the relative contributions of IFN-α and IFN-β to filovirus pathogenesis in animal models and humans. Finally, we evaluate the putative utilization of IFN-I in post-exposure therapy and its implications as a biomarker of vaccine efficacy.

scholarly journals The Generation and Regulation of Tissue-Resident Tregs and Their Role in Autoimmune Diseases

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Shuang Wang ◽  
Xueyang Zou ◽  
Yi Zhang ◽  
Xiaoya Wang ◽  
Wei Yang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
T Cells ◽  
Immune Responses ◽  
Autoimmune Diseases ◽  
Hot Spot ◽  
Exploratory Stage ◽  
And Function

Regulatory T cells (Tregs), as an important subset of T cells, play an important role in maintaining body homeostasis by regulating immune responses and preventing autoimmune diseases. In-depth research finds that Tregs have strong instability and plasticity, and according to their developmental origin, Tregs can be classified into thymic-derived Tregs (tTregs), endogenous-induced Tregs (pTregs), which are produced by antigen-stimulated T cells in the periphery in vivo, and induced Tregs (iTregs), which differentiate from naïve T cells in vitro. In recent years, studies have found that Tregs are divided into lymphatic and tissue-resident Tregs according to their location. Research on the generation and function of lymphoid Tregs has been more comprehensive and thorough, but the role of tissue Tregs is still in the exploratory stage, and it has become a research hot spot. In this review, we discuss the instability and plasticity of Tregs and the latest developments of tissue-resident Tregs in the field of biology, including adipose tissue, colon, skeletal muscle, and other Tregs that have been recently discovered as well as their production, regulation, and function in specific tissues and their role in the pathogenesis of autoimmune diseases.

EXTH-21. MECHANISMS OF SYNERGISTIC GROWTH SUPPRESSION BY RADIOTHERAPY AND C-MET INHIBITION IN EXPERIMENTAL GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi167-vi168
Author(s):  
Manuela Silginer ◽  
Eleanna Papa ◽  
Emese Szabo ◽  
Flavio Vasella ◽  
Patrick Roth ◽  
...  
Keyword(s):  
Immune Responses ◽  
Synergistic Effects ◽  
Glioma Cells ◽  
Immunodeficient Mice ◽  
Glioma Growth ◽  
Pathway Inhibition ◽  
Murine Glioma

Abstract Glioblastoma remains to be one of the most lethal solid cancers and novel therapies are urgently needed. There is increasing interest in the role of the HGF/MET pathway in the response of glioblastoma to radiotherapy. c-MET-mediated radioresistance may be partially induced via proinvasive and DNA damageresponse pathways and HGF may be involved in the regulation of immune responses. Here, we explored the role of the c-MET pathway in response to radiotherapy and investigated potential modes of action that mediate synergistic effects of MET pathway inhibition and irradiation in syngeneic murine glioma models in vitro and in vivo. Murine glioma cells express HGF and c-MET and respond with c-MET phosphorylation upon exposure to exogenous HGF. In vitro, glioma cell viability and proliferation are not affected by pharmacological or genetic c-MET pathway interference, and the c-MET inhibitor tepotinib fails to sensitize glioma cells to irradiation. Conversely, in vivo c-MET inhibition combined with focal radiotherapy synergistically prolongs survival in two syngeneic orthotopic glioma models compared with either treatment alone. Complementary studies demonstrated that synergy was lost when gliomas were established and treated in immunodeficient mice, and importantly, also when c-MET gene expression was disrupted in the tumor. Thus, synergistic suppression of experimental syngeneic glioma growth by irradiation and c-MET inhibition requires at least two mechanisms, expression of c-MET in the tumor and a functional immune system. In summary, our data suggest clinical evaluation of c-MET pathway inhibition in combination with radiotherapy in human glioblastoma.

Enhanced β-Catenin/Foxo1 Activity Alleviates Pulmonary Fibrosis by Inhibiting β-Catenin/T Cell Factor Signaling

2020 ◽  
Vol 10 (2) ◽  
pp. 182-188
Author(s):  
Kun Gui ◽  
Yu Huang ◽  
Meijin Wang ◽  
Jun Yang
Keyword(s):  
Extracellular Matrix ◽  
Pulmonary Fibrosis ◽  
Inflammatory Cytokines ◽  
Underlying Mechanism ◽  
Control Group ◽  
Kidney Fibrosis ◽  
Mrc5 Cell

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia, resulting in chronic respiratoryfailure and eventually death. β-catenin/Foxo1 showed a protective property in kidney fibrosis, but the role of β-catenin/Foxo1 in IPF was unclear. Our study aimed to investigate the role of β-catenin/Foxo1 in IPF and explore its underlying mechanism. The IPF model was established by injection of bleomycin (BLM) in vivo and stimulation by TGF-β1 in MRC5 cell in vitro. Haematoxylin-eosin staining and Masson’s trichrome staining were performed to examine histopathological injury in lung. Protein expression of corresponding genes was detected using western blot. Immunofluorescence staining assay was carried out to detect the expression of β-catenin, Foxo1, TCF and α-SMA. The expression levels of inflammatory cytokines were determined using ELISA kit assay. The results showed that BLM induced a serious pulmonary injury and proliferated fibroblasts. A higher interaction of β-catenin with TCF and a lower interaction of β-catenin with Foxo1 was found in BLM group compared to the control group. TGF-β1 promoted β-catenin/TCF, whereas ICG-001 inhibited β-catenin/TCF, and promoted β-catenin/Foxo1. Furthermore, ICG-001 reversed TGF-β1 induced largely production of inflammatory cytokines and accumulation of extracellular matrix, as well as high expression of α-SMA. However, AS1842856, a FOXO1 antagonist, strengthened the effects induced by TGF-β1. In summary, our study revealed that β-catenin/Foxo1 protected against IPF through inhibiting inflammatory response and extracellular matrix accumulation, providing an alternative approach to explain the potential mechanism of IPF and seek for more effective therapeutic drugs.

in vivo and in vitro analysis of the functional role of Epstein-Barr virus-induced gene 3 (EBI3) for regulation of Th2 mediated immune responses

2003 ◽  
Vol 124 (4) ◽  
pp. A335
Author(s):  
Stefan J. Wirtz ◽  
Christoph Becker ◽  
Edward E.S. Nieuwenhuis ◽  
Mark Birkenbach ◽  
Richard S. Blumberg ◽  
...  
Keyword(s):  
Immune Responses ◽  
Functional Role ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr ◽  
Vitro Analysis ◽  
In Vitro Analysis

scholarly journals Irisin alleviates obesity-related spermatogenesis dysfunction via the regulation of the AMPKα signalling pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yang Mu ◽  
Huang-Guan Dai ◽  
Ling-Bo Luo ◽  
Jing Yang
Keyword(s):  
Oxidative Stress ◽  
Sperm Count ◽  
Underlying Mechanism ◽  
Signalling Pathway ◽  
Protective Effects ◽  
Exercise Induced ◽  
Amp Activated Protein Kinase

Abstract Background Infertility is a common complication in obese men. Oxidative stress and testicular apoptosis play critical roles in obesity-induced spermatogenesis dysfunction. It has been reported that irisin, an exercise-induced myokine, may attenuate oxidative damage and testicular apoptosis in several diseases; however, its role in obesity-induced spermatogenesis dysfunction remains unclear. The purpose of this study was to investigate the role and underlying mechanism of irisin in obesity-induced dysfunction of spermatogenesis. Methods Male mice were fed a high-fat diet (HFD) for 24 weeks to establish a model of obesity-induced spermatogenesis dysfunction. To explore the effects of irisin, mice were subcutaneously infused with recombinant irisin for 8 weeks beginning at 16 weeks after starting a HFD. To confirm the role of AMP-activated protein kinase α (AMPKα), AMPKα-deficient mice were used. Results The data showed decreased serum irisin levels in obese patients, which was negatively correlated with sperm count and progressive motility. Irisin was downregulated in the plasma and testes of obese mice. Supplementation with irisin protected against HFD-induced spermatogenesis dysfunction and increased testosterone levels in mice. HFD-induced oxidative stress, endoplasmic reticulum (ER) stress and testicular apoptosis were largely attenuated by irisin treatment. Mechanistically, we identified that irisin activated the AMPKα signalling pathway. With AMPKα depletion, we found that the protective effects of irisin on spermatogenesis dysfunction were abolished in vivo and in vitro. Conclusions In conclusion, we found that irisin alleviated obesity-related spermatogenesis dysfunction via activation of the AMPKα signalling pathway. Based on these findings, we hypothesized that irisin is a potential therapeutic agent against obesity-related spermatogenesis dysfunction.

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