Lipopolysaccharide Binds Platelet Toll-Like Receptor 4 and Mediates the Activation of Phagocytes in the Reticuloendothelial System (RES): A Novel Mechanism of Host Immunity.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1093-1093
Author(s):  
John W. Semple ◽  
Rukhsana Aslam ◽  
Edwin R. Speck ◽  
John Freedman
Keyword(s):  
Flow Cytometric Analysis ◽  
Reticuloendothelial System ◽  
Tlr4 Expression ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Tnf Α ◽  
Multiple Copies ◽  
Factor Α

Abstract Toll-like receptors (TLR) comprise a family of transmembrane proteins characterized by multiple copies of leucine-rich repeats in the extracellular domain and an IL-1 receptor motif in their cytoplasmic domain. The TLR family is a phylogenetically conserved mediator of innate immunity that is essential for microbial recognition and the stimulation of adaptive immune responses. Recently, our laboratory demonstrated that TLR4 expression on platelets was responsible for lipopolysaccharide (LPS)-mediated thrombocytopenia and tumour necrosis factor-α production in vivo (Aslam et al. Blood107:637, 2006). To understand the mechanism of how platelet TLR4 may mediate RES activation, platelets from wild type (WT) and TLR4 knockout mice were incubated with various concentrations of LPS in vitro, washed extensively and transfused into WT mice. Results suggest that only the WT platelets could significantly stimulate TNF-α production in vivo. In vitro flow cytometric analysis of phagocytosis by the monocytic cell line THP-1 demonstrated that platelet TLR4 could efficiently present LPS to THP-1 cells and stimulated them to engulf the LPS-coated platelets. The phagocytosis of the platelets was correlated to elevated levels of intracellular TNF-α production in the THP-1 cells. These results suggest that platelets, via TLR4 expression, can act as initial sentinels of the innate immune system by presenting bacterial products such as LPS to phagocytes of the RES.

scholarly journals Modified Vaccinia Virus Ankara Triggers Chemotaxis of Monocytes and Early Respiratory Immigration of Leukocytes by Induction of CCL2 Expression

2009 ◽  
Vol 83 (6) ◽  
pp. 2540-2552 ◽  
Author(s):  
Michael H. Lehmann ◽  
Wolfgang Kastenmuller ◽  
Judith D. Kandemir ◽  
Florian Brandt ◽  
Yasemin Suezer ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Viral Vector ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Human Monocytic Cell Line ◽  
Modified Vaccinia Virus Ankara ◽  
Ccl2 Expression ◽  
Human Monocytic Cell

ABSTRACT Orthopoxviruses commonly enter into humans and animals via the respiratory tract. Herein, we show that immigration of leukocytes into the lung is triggered via intranasal infection of mice with modified vaccinia virus Ankara (MVA) and not with the vaccinia virus (VACV) Elstree, Wyeth, or Western Reserve (WR) strain. Immigrating cells were identified as monocytes, neutrophils, and CD4+ lymphocytes by flow cytometry and could be detected 24 h and 48 h postinfection. Using an in vitro chemotaxis assay, we confirmed that infection with MVA induces the expression of a soluble chemotactic factor for monocytes, identified as CCL2 (monocyte chemotactic protein-1 [MCP-1]). In contrast to infection with several other VACV strains, MVA induced the expression of CCL2, CCL3, CCL4, and CXCL10 in the human monocytic cell line THP-1 as well as in primary human monocytes. Thus, MVA, and not the VACV Elstree, Wyeth, or WR strain, consistently triggered the expression of a panel of chemokines, including CCL2, in the murine lung, correlating considerably with the immigration of leukocytes. Using CCL2-deficient mice, we demonstrate that CCL2 plays a key role in MVA-triggered respiratory immigration of leukocytes. Moreover, UV irradiation of MVA prevented CCL2 expression in vitro and in vivo as well as respiratory immigration of leukocytes, demonstrating the requirement for an activated molecular viral life cycle. We propose that MVA-triggered chemokine expression causes early immigration of leukocytes to the site of infection, a feature that is important for rapid immunization and its safety and efficiency as a viral vector.

scholarly journals L-Selectin–Dependent Leukocyte Adhesion to Microvascular But Not to Macrovascular Endothelial Cells of the Human Coronary System

Blood ◽  
1997 ◽  
Vol 89 (9) ◽  
pp. 3228-3235 ◽  
Author(s):  
A. Zakrzewicz ◽  
M. Gräfe ◽  
D. Terbeek ◽  
M. Bongrazio ◽  
W. Auch-Schwelk ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Time Course ◽  
Leukocyte Adhesion ◽  
Flow Chamber ◽  
Shear Stresses ◽  
Selectin Ligands ◽  
Tnf Α ◽  
Factor Α

Abstract To characterize L-selectin–dependent cell adhesion to human vascular endothelium, human cardiac microvascular endothelial cells (HCMEC) and human coronary endothelial cells (HCEC) were isolated from explanted human hearts. The adhesion behavior of human (NALM-6) and mouse (300.19) pre-B cells transfected with cDNA encoding for human L-selectin was compared with that of the respective nontransfected cells in a flow chamber in vitro. More than 80% of the adhesion to tumor necrosis factor-α (TNF-α)–stimulated HCMEC at shear stresses <2 dyne/cm2 was L-selectin dependent and could be equally well blocked by an anti–L-selectin antibody or a L-selectin-IgG-chimera. No L-selectin dependent adhesion to HCEC could be shown. The L-selectin dependent adhesion to HCMEC was insensitive to neuraminidase, but greatly inhibited by addition of NaClO3 , which inhibits posttranslational sulfation and remained elevated for at least 24 hours of stimulation. E-selectin dependent adhesion of HL60 cells to HCMEC was blocked by neuraminidase, but not by NaClO3 and returned to control levels within 18 hours of HCMEC stimulation. It is concluded that microvascular, but not macrovascular endothelial cells express TNF-α–inducible sulfated ligand(s) for L-selectin, which differ from known L-selectin ligands, because sialylation is not required. The prolonged time course of L-selectin dependent adhesion suggests a role in sustained leukocyte recruitment into inflammatory sites in vivo.

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.

TNF-α and myocardial depression in endotoxemic rats: temporal discordance of an obligatory relationship

1998 ◽  
Vol 275 (2) ◽  
pp. R502-R508 ◽  
Author(s):  
Xianzhong Meng ◽  
Lihua Ao ◽  
Daniel R. Meldrum ◽  
Brian S. Cain ◽  
Brian D. Shames ◽  
...  
Keyword(s):  
Temporal Relationship ◽  
Contractile Function ◽  
Myocardial Depression ◽  
Tnf Α ◽  
Myocardial Contractile ◽  
Factor Α ◽  
Relationship Of

Exogenous tumor necrosis factor-α (TNF-α) induces delayed myocardial depression in vivo but promotes rapid myocardial depression in vitro. The temporal relationship between endogenous TNF-α and endotoxemic myocardial depression is unclear, and the role of TNF-α in this myocardial disorder remains controversial. Using a rat model of endotoxemia not complicated by shock, we sought to determine 1) the temporal relationship of changes in circulating and myocardial TNF-α with myocardial depression, 2) the influences of protein synthesis inhibition or immunosuppression on TNF-α production and myocardial depression, and 3) the influence of neutralization of TNF-α on myocardial depression. Rats were treated with lipopolysaccharide (LPS, 0.5 mg/kg ip). Circulating and myocardial TNF-α increased at 1 and 2 h, whereas myocardial contractility was depressed at 4 and 6 h. Pretreatment with cycloheximide or dexamethasone abolished the increase in circulating and myocardial TNF-α and preserved myocardial contractile function. Similarly, treatment with TNF binding protein immediately after LPS prevented myocardial depression. We conclude that endogenous TNF-α mediates delayed myocardial depression in endotoxemic rats and that inhibition of TNF-α production or neutralization of TNF-α preserves myocardial contractile function in endotoxemia.

Nonstressed rat model of acute endotoxemia that unmasks the endotoxin-induced TNF-α response

1999 ◽  
Vol 276 (2) ◽  
pp. H671-H678 ◽  
Author(s):  
David W. A. Beno ◽  
Robert E. Kimura
Keyword(s):  
Rat Model ◽  
Endotoxic Shock ◽  
Stress Hormones ◽  
Tnf Α ◽  
Baseline Concentrations ◽  
Experimental Protocols ◽  
Factor Α ◽  
Necrosis Factor

Previous investigators have demonstrated that the tumor necrosis factor-α (TNF-α) response to endotoxin is inhibited by exogenous corticosterone or catecholamines both in vitro and in vivo, whereas others have reported that surgical and nonsurgical stress increase the endogenous concentrations of these stress-induced hormones. We hypothesized that elevated endogenous stress hormones resultant from experimental protocols attenuated the endotoxin-induced TNF-α response. We used a chronically catheterized rat model to demonstrate that the endotoxin-induced TNF-α response is 10- to 50-fold greater in nonstressed (NS) rats compared with either surgical-stressed (SS, laparotomy) or nonsurgical-stressed (NSS, tail vein injection) models. Compared with the NS group, the SS and NSS groups demonstrated significantly lower mean peak TNF-α responses at 2 mg/kg and 6 μg/kg endotoxin [NS 111.8 ± 6.5 ng/ml and 64.3 ± 5.9 ng/ml, respectively, vs. SS 3.9 ± 1.1 ng/ml ( P < 0.01) and 1.3 ± 0.5 ng/ml ( P < 0.01) or NSS 5.2 ± 3.2 ng/ml ( P < 0.01) at 6 μg/kg]. Similarly, baseline concentrations of corticosterone and catecholamines were significantly lower in the NSS group [84.5 ± 16.5 ng/ml and 199.8 ± 26.2 pg/ml, respectively, vs. SS group 257.2 ± 35.7 ng/ml ( P< 0.01) and 467.5 ± 52.2 pg/ml ( P < 0.01) or NS group 168.6 ± 14.4 ng/ml ( P < 0.01) and 1,109.9 ± 140.7 pg/ml ( P < 0.01)]. These findings suggest that the surgical and nonsurgical stress inherent in experimental protocols increases baseline stress hormones, masking the endotoxin-induced TNF-α response. Subsequent studies of endotoxic shock should control for the effects of protocol-induced stress and should measure and report baseline concentrations of corticosterone and catecholamines.

Regulation of granulocyte apoptosis by NF-κB

2004 ◽  
Vol 32 (3) ◽  
pp. 465-467 ◽  
Author(s):  
C. Ward ◽  
A. Walker ◽  
I. Dransfield ◽  
C. Haslett ◽  
A.G. Rossi
Keyword(s):  
Nuclear Factor Κb ◽  
Resolution Of Inflammation ◽  
Tnf Α ◽  
Successful Resolution ◽  
Factor Α ◽  
Apoptotic Effects ◽  
Second Wave ◽  
Crucial Part

Granulocyte apoptosis is a crucial part of the successful resolution of inflammation. In vitro results show that activation of NF-κB (nuclear factor κB) in granulocytes is a survival mechanism. NF-κB inhibitors increase the rate of constitutive apoptosis in neutrophils and eosinophils and cause these cells to respond to the pro-apoptotic effects of TNF-α (tumour necrosis factor-α). Results from both in vivo and in vitro experiments suggest that there are at least two important waves of NF-κB activation in inflammatory loci, which increase the expression of COX-2 (cyclooxygenase-2), itself an NF-κB controlled gene. The first wave causes the production of inflammatory mediators such as PGE2 (prostaglandin E2), allowing the establishment of inflammation. The second wave causes the synthesis of PGD2 and its metabolites that induce granulocyte apoptosis by inhibiting NF-κB activation. These metabolites may therefore be important physiological mediators controlling the resolution of inflammation. Although NF-κB is an important target for anti-inflammatory therapy, the timing of inhibition in vivo may be crucial, to ensure that production of PGD2 and its sequential metabolites can occur.

A novel fluorinated stilbene exerts hepatoprotective properties in CCl4-induced acute liver damage

2011 ◽  
Vol 89 (10) ◽  
pp. 759-766 ◽  
Author(s):  
Horacio Rivera ◽  
Martha S. Morales-Ríos ◽  
Wendy Bautista ◽  
Mineko Shibayama ◽  
Víctor Tsutsumi ◽  
...  
Keyword(s):  
Liver Damage ◽  
Inflammatory Responses ◽  
Acute Liver Damage ◽  
Tnf Α ◽  
Male Wistar Rats ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Glutamyl Transpeptidase

There has been a recently increase in the development of novel stilbene-based compounds with in vitro anti-inflamatory properties. For this study, we synthesized and evaluated the anti-inflammatory properties of 2 fluorinated stilbenes on carbon tetrachloride (CCl4)-induced acute liver damage. To achieve this, CCl4 (4 g·kg–1, per os) was administered to male Wistar rats, followed by either 2-fluoro-4′-methoxystilbene (FME) or 2,3-difluoro-4′-methoxystilbene (DFME) (10 mg·kg–1, per os). We found that although both of the latter compounds prevented cholestatic damage (γ-glutamyl transpeptidase activity), only DFME showed partial but consistent results in the prevention of necrosis, as assessed by both alanine aminotransferase activity and histological analysis. Since inflammatory responses are mediated by cytokines, mainly tumour necrosis factor α (TNF-α), we used the Western blot technique to determine the action of FME and DFME on the expression level of this cytokine. The observed increase in the level of TNF-α caused by CCl4 administration was only prevented by treatment with DFME, in agreement with our biochemical findings. This result was confirmed by measuring interleukin-6 (IL-6) levels, since the expression of this protein depends on the level of TNF-α. In this case, DFME completely blocked the CCl4-induced increase of IL-6. Our results suggest that DFME possesses greater anti-inflammatory properties in vivo than FME. DFME constitutes a possible therapeutic agent for liver disease and could serve as a template for structure optimization.

An Anti-c-Fms Antibody Inhibits Orthodontic Tooth Movement

2008 ◽  
Vol 87 (4) ◽  
pp. 396-400 ◽  
Author(s):  
H. Kitaura ◽  
M. Yoshimatsu ◽  
Y. Fujimura ◽  
T. Eguchi ◽  
H. Kohara ◽  
...  
Keyword(s):  
Mechanical Loading ◽  
Tooth Movement ◽  
Bone Erosion ◽  
Orthodontic Tooth Movement ◽  
Movement Model ◽  
Tnf Α ◽  
Macrophage Colony ◽  
Factor Α

Orthodontic force induces osteoclastogenesis in vivo. It has recently been reported that administration of an antibody against the macrophage-colony-stimulating factor (M-CSF) receptor c-Fms blocks osteoclastogenesis and bone erosion induced by tumor necrosis factor-α (TNF-α) administration. This study aimed to examine the effect of an anti-c-Fms antibody on mechanical loading-induced osteoclastogenesis and osteolysis in an orthodontic tooth movement model in mice. Using TNF receptor 1- and 2-deficient mice, we showed that orthodontic tooth movement was mediated by TNF-α. We injected anti-c-Fms antibody daily into a local site, for 12 days, during mechanical loading. The anti-c-Fms antibody significantly inhibited orthodontic tooth movement, markedly reduced the number of osteoclasts in vivo, and inhibited TNF-α-induced osteoclastogenesis in vitro. These findings suggest that M-CSF plays an important role in mechanical loading-induced osteoclastogenesis and bone resorption during orthodontic tooth movement mediated by TNF-α.

Anti-Oxidative and Anti-Inflammatory Effects of Lobelia chinensis In Vitro and In Vivo

2015 ◽  
Vol 43 (02) ◽  
pp. 269-287 ◽  
Author(s):  
Kun-Cheng Li ◽  
Yu-Ling Ho ◽  
Guan-Jhong Huang ◽  
Yuan-Shiun Chang
Keyword(s):  
Nitric Oxide ◽  
Folk Medicine ◽  
Ethyl Acetate Fraction ◽  
Raw264.7 Macrophages ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Factor Α

Lobelia chinensis Lour (LcL) is a popular herb that has been widely used as folk medicine in China for the treatment of fever, lung cancer, and inflammation for hundreds of years. Recently, several studies have shown that the anti-inflammatory properties were correlated with the inhibition of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) from the NF-κB pathway. The aim of this study was to evaluate the anti-oxidative and anti-inflammatory activities of L. chinensis. Both suppressive activities on LPS-induced nitric oxide production in RAW264.7 macrophages in vitro and the acute rat lung injury model in vivo were studied. The results showed that the methanol extract of LcL and its fractions within the range of 62.5–250 μg/mL did not induce cytotoxicity (p < 0.001). The ethyl acetate fraction of LcL showed better NO inhibition activity than other fractions. On the other hand, the Lc-EA (62.5, 125, 250 mg/kg) pretreated rats showed a decrease in the pro-inflammatory cytokines (TNF-α, IL-β, IL-6) and inhibited iNOS, COX-2 expression through the NF-κB pathway. These results suggested that L. chinensis exhibited an anti-inflammatory effect through the NF-κB pathways.

scholarly journals Remimazolam Protects Against LPS-Induced Endotoxicity Improving Survival of Endotoxemia Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaolei Liu ◽  
Shaoping Lin ◽  
Yiyue Zhong ◽  
Jiaojiao Shen ◽  
Xuedi Zhang ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Signal Pathway ◽  
Tlr4 Expression ◽  
Tnf Α ◽  
Sedative Drugs ◽  
Mapk Signal Pathway ◽  
Lps Treatment

Remimazolam is a new benzodiazepine of sedative drugs with an ultra-short-acting anesthetic effect, commonly used for critically ill patients (especially septic patients) in intensive care units (ICUs). Although some anesthetics have been reported to show certain anti-inflammatory effects, the role of remimazolam in inflammation is still remained unknown. Here, we studied the effects of remimazolam on macrophage in response to LPS both in vivo and in vitro. Interestingly, compared with LPS treatment group, remimazolam remarkably improved survival rate of endotoxemia mice and decreased the release of LPS-induced inflammatory mediators (such as TNF-α, IL-6, and IL-1β). We further found that remimazolam not only inhibited the activation of MAPK signal pathway at 15 min after LPS treatment but also disturbed Rab5a related TLR4 expression at cell surface in response to LPS at a later time. Such evidence suggests that remimazolam might be beneficial to septic patients who are suffering from uncontrolled inflammatory responses.

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