scholarly journals Activation of TLR4-Mediated NFB Signaling in Hemorrhagic Brain in Rats

2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
Author(s):  
Weiyu Teng ◽  
Lishu Wang ◽  
Weishuang Xue ◽  
Chao Guan
Keyword(s):  
Inflammatory Responses ◽  
Saline Control ◽  
Toll Like Receptor ◽  
Rt Pcr ◽  
Cerebral Tissue ◽  
Toll Like Receptor 4 ◽  
Western Blots ◽  
Tlr4 Mrna ◽  
Injured Brain ◽  
The Brain

Inflammation and immunity play a crucial role in the pathogenesis of Intracerebral hemorrhage (ICH). Toll-like receptor 4- (TLR4-) mediated nuclear factor kappa-B (NFB) signaling plays critical roles in the activation and regulation of inflammatory responses in injured brain. However, the involvement of TLR4-mediated NFB signaling in the pathogenesis of ICH remains unknown. The present study was to evaluate the temporal profile of the expression of TLR4 and the activation of TLR4-mediated NFB signaling in brain tissues of Wistar rats after ICH. TLR4 mRNA and protein, the phosphorylation of inhibitors of kappa B (p-IB), and the activity of NFB were examined in hemorrhagic cerebral tissue by Rt-PCR, Western blots, immunohistochemistry staining, and EMSA. Compared with saline control, the TLR4 mRNA and protein significantly increased starting at 6 hours after ICH, peaked on the 3rd day after ICH, and then decreased but still maintained at a higher level on the 7th day after ICH (). The level of p-IB and the activity of NFB also increased in the brain after ICH compared with saline control. The present study firstly suggests that TLR4-mediated NFB signaling participates in the pathogenesis of ICH, which may become a therapeutic target for ICH-induced brain damage.

Abstract 201: Mice Lacking the Gene for Toll-like Receptor 4 (TLR4) Had an Attenuated ER Stress in the Heart in Response to Ang II Infusion

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Rahul Dange ◽  
Anand R. Nair ◽  
Jorge Vila ◽  
Philip J Ebenezer ◽  
Joseph Francis
Keyword(s):  
Cardiac Hypertrophy ◽  
Er Stress ◽  
Left Ventricular ◽  
Ang Ii ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Rt Pcr ◽  
Toll Like Receptor 4 ◽  
Knock Out ◽  
The Brain

Inflammatory molecule plays an important role in the pathophysiology of hypertension. Recently we showed that TLR4 inhibition in the brain attenuates hypertension. In this study we demonstrate that ANGII induced ER stress in the heart is attenuated in mice lacking the gene for TLR4. In addition, we show that ANGII induced cardiac hypertrophy is blocked by ER stress inhibitor. Method: TLR4 knock-out (KO) mice and wild type (WT) controls were implanted with telemetry probes for mean arterial pressure (MAP) measurements. After collecting baseline MAP and left ventricular function using echocardiography, osmotic minipump containing ANGII (200ng/kg/min) or vehicle (saline) was implanted for 14 days. In another group, C57BL6 mice were injected with ER stress inhibitor 4-PBA (150mg/kg bw) given intraperitoneally with and without ANGII. At the end of the study, mice were sacrificed the LV tissue removed and analyzed for gene of interest using RT-PCR and Western blotting. Results are tabulated. The real-time PCR values are shown as αCT values (18S - the gene of interest). Conclusions: 1) ANGII infusion induces cardiac hypertrophy and ER stress. 2) Mice lacking the gene for TLR4 had attenuated cardiac hypertrophy and ER stress in response to ANGII. 3) ER stress inhibitor protect against ANGII induces cardiac hypertrophy. 4) TLR4 at least in part contributes to ANG II induced cardiac hypertrophy and ER stress.

scholarly journals Serum Amyloid A1/Toll-Like Receptor-4 Axis, an Important Link between Inflammation and Outcome of TBI Patients

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 599
Author(s):  
Víctor Farré-Alins ◽  
Alejandra Palomino-Antolín ◽  
Paloma Narros-Fernández ◽  
Ana Belen Lopez-Rodriguez ◽  
Céline Decouty-Perez ◽  
...  
Keyword(s):  
Injury Severity ◽  
White Blood Cells ◽  
Serum Amyloid ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Important Link ◽  
Tlr4 Mrna ◽  
Serum Amyloid A1

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide without any validated biomarker or set of biomarkers to help the diagnosis and evaluation of the evolution/prognosis of TBI patients. To achieve this aim, a deeper knowledge of the biochemical and pathophysiological processes triggered after the trauma is essential. Here, we identified the serum amyloid A1 protein-Toll-like receptor 4 (SAA1-TLR4) axis as an important link between inflammation and the outcome of TBI patients. Using serum and mRNA from white blood cells (WBC) of TBI patients, we found a positive correlation between serum SAA1 levels and injury severity, as well as with the 6-month outcome of TBI patients. SAA1 levels also correlate with the presence of TLR4 mRNA in WBC. In vitro, we found that SAA1 contributes to inflammation via TLR4 activation that releases inflammatory cytokines, which in turn increases SAA1 levels, establishing a positive proinflammatory loop. In vivo, post-TBI treatment with the TLR4-antagonist TAK242 reduces SAA1 levels, improves neurobehavioral outcome, and prevents blood–brain barrier disruption. Our data support further evaluation of (i) post-TBI treatment in the presence of TLR4 inhibition for limiting TBI-induced damage and (ii) SAA1-TLR4 as a biomarker of injury progression in TBI patients.

scholarly journals Biofilm Growth Increases Phosphorylcholine Content and Decreases Potency of Nontypeable Haemophilus influenzae Endotoxins

2006 ◽  
Vol 74 (3) ◽  
pp. 1828-1836 ◽  
Author(s):  
Shayla West-Barnette ◽  
Andrea Rockel ◽  
W. Edward Swords
Keyword(s):  
Haemophilus Influenzae ◽  
Inflammatory Responses ◽  
Opportunistic Pathogen ◽  
Host Responses ◽  
Toll Like Receptor ◽  
Nontypeable Haemophilus Influenzae ◽  
Toll Like Receptor 4 ◽  
Biofilm Growth ◽  
Bacterial Endotoxins ◽  
Cell Layers

ABSTRACT Nontypeable Haemophilus influenzae (NTHI) is a common respiratory commensal and opportunistic pathogen. NTHI is normally contained within the airways by host innate defenses that include recognition of bacterial endotoxins by Toll-like receptor 4 (TLR4). NTHI produces lipooligosaccharide (LOS) endotoxins which lack polymeric O side chains and which may contain host glycolipids. We recently showed that NTHI biofilms contain variants with sialylated LOS glycoforms that are essential to biofilm formation. In this study, we show that NTHI forms biofilms on epithelial cell layers. Confocal analysis revealed that sialylated variants were distributed throughout the biofilm, while variants expressing phosphorylcholine (PCho) were found within the biofilm. Consistent with this observation, PCho content of LOS purified from NTHI biofilms was increased compared to LOS from planktonic cultures. Hypothesizing that the observed changes in endotoxin composition could affect bioactivity, we compared inflammatory responses to NTHI LOS purified from biofilm and planktonic cultures. Our results show that endotoxins from biofilms induced weaker host innate responses. While we observed a minimal effect of sialylation on LOS bioactivity, there was a significant decrease in bioactivity associated with PCho substitutions. We thus conclude that biofilm growth increases the proportion of PCho+ variants in an NTHI population, resulting in a net decrease in LOS bioactivity. Thus, in addition to their well-documented resistance phenotypes, our data show that biofilm communities of NTHI bacteria contain variants that evoke less potent host responses.

Toll-like receptor 4 and CD14 mRNA expression are lower in resistive exercise-trained elderly women

2003 ◽  
Vol 95 (5) ◽  
pp. 1833-1842 ◽  
Author(s):  
Michael G. Flynn ◽  
Brian K. McFarlin ◽  
Melody D. Phillips ◽  
Laura K. Stewart ◽  
Kyle L. Timmerman
Keyword(s):  
Mrna Expression ◽  
Group Effect ◽  
Toll Like Receptor ◽  
Significant Group Effect ◽  
Toll Like Receptor 4 ◽  
Significant Group ◽  
Resistive Exercise ◽  
Tlr4 Mrna ◽  
Tnf Α ◽  
Cd14 Mrna

The purpose of this study was to examine the influence of resistive exercise training and hormone status on mRNA expression of toll-like receptor 4 (TLR4), CD14, IL-1β, IL-6, and TNF-α. Resistive exercise-trained women on “traditional” hormone replacements [hormone replacement therapy (HRT), n = 9], not taking hormones (NHR, n = 6), or taking medications known to influence bone (MIB, n = 7) were compared with untrained subjects not taking supplemental hormones (Con, n = 6). Blood was taken from trained subjects before, immediately after, and 2 h after resistive exercise (same time points for resting Con). TLR4 mRNA expression (RT-PCR) was not different among groups or across time but was significantly ( P = 0.044) lower (1.9-fold) when trained groups were collapsed and compared with Con. There was also a significant group effect ( P < 0.0001) for TLR4 mRNA when expressed per monocyte. CD14 expression was significantly ( P = 0.006) lower (2.3-fold) for training groups collapsed and compared with Con. CD14 mRNA, expressed per monocyte, was significantly lower immediately after resistive exercise for NHR, HRT, and MIB compared with Con. There were few significant effects detected for IL-6, IL-1β, and TNF-α mRNA, but there was a significant group effect ( P < 0.0001) for TNF-α mRNA expressed per monocyte (Con > HRT, NHR, MIB). These findings suggest that there may be a resistive exercise training-induced reduction in TLR4/CD14 expression in older women. Further research is needed to determine whether lower TLR4/CD14 could explain the lower LPS-stimulated inflammatory cytokines observed in these women.

scholarly journals Neuropharmacological Potential ofGastrodia elataBlume and Its Components

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Jung-Hee Jang ◽  
Yeonghoon Son ◽  
Seong Soo Kang ◽  
Chun-Sik Bae ◽  
Jong-Choon Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Function ◽  
Intracellular Signaling ◽  
Inflammatory Responses ◽  
Signaling Cascades ◽  
Sedative Medication ◽  
Synthetic Chemicals ◽  
Injured Brain ◽  
Injury Models ◽  
The Brain

Research has been conducted in various fields in an attempt to develop new therapeutic agents for incurable neurodegenerative diseases.Gastrodia elataBlume (GE), a traditional herbal medicine, has been used in neurological disorders as an anticonvulsant, analgesic, and sedative medication. Several neurodegenerative models are characterized by oxidative stress and inflammation in the brain, which lead to cell death via multiple extracellular and intracellular signaling pathways. The blockade of certain signaling cascades may represent a compensatory therapy for injured brain tissue. Antioxidative and anti-inflammatory compounds isolated from natural resources have been investigated, as have various synthetic chemicals. Specifically, GE rhizome extract and its components have been shown to protect neuronal cells and recover brain function in various preclinical brain injury models by inhibiting oxidative stress and inflammatory responses. The present review discusses the neuroprotective potential of GE and its components and the related mechanisms; we also provide possible preventive and therapeutic strategies for neurodegenerative disorders using herbal resources.

scholarly journals Human resistin protects against endotoxic shock by blocking LPS–TLR4 interaction

2017 ◽  
Vol 114 (48) ◽  
pp. E10399-E10408 ◽  
Author(s):  
Jessica C. Jang ◽  
Jiang Li ◽  
Luca Gambini ◽  
Hashini M. Batugedara ◽  
Sandeep Sati ◽  
...  
Keyword(s):  
Immune Cell ◽  
Inflammatory Responses ◽  
Endotoxic Shock ◽  
Critical Role ◽  
Nippostrongylus Brasiliensis ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Therapeutic Function ◽  
Human Immune ◽  
Human Resistin

Helminths trigger multiple immunomodulatory pathways that can protect from sepsis. Human resistin (hRetn) is an immune cell-derived protein that is highly elevated in helminth infection and sepsis. However, the function of hRetn in sepsis, or whether hRetn influences helminth protection against sepsis, is unknown. Employing hRetn-expressing transgenic mice (hRETNTg+) and recombinant hRetn, we identify a therapeutic function for hRetn in lipopolysaccharide (LPS)-induced septic shock. hRetn promoted helminth-induced immunomodulation, with increased survival of Nippostrongylus brasiliensis (Nb)-infected hRETNTg+ mice after a fatal LPS dose compared with naive mice or Nb-infected hRETNTg− mice. Employing immunoprecipitation assays, hRETNTg+Tlr4−/− mice, and human immune cell culture, we demonstrate that hRetn binds the LPS receptor Toll-like receptor 4 (TLR4) through its N terminal and modulates STAT3 and TBK1 signaling, triggering a switch from proinflammatory to anti-inflammatory responses. Further, we generate hRetn N-terminal peptides that are able to block LPS proinflammatory function. Together, our studies identify a critical role for hRetn in blocking LPS function with important clinical significance in helminth-induced immunomodulation and sepsis.

Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-γ: a molecular basis for priming and synergism with bacterial lipopolysaccharide

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3427-3431 ◽  
Author(s):  
Daniela Bosisio ◽  
Nadia Polentarutti ◽  
Marina Sironi ◽  
Sergio Bernasconi ◽  
Kensuke Miyake ◽  
...  
Keyword(s):  
Surface Expression ◽  
Interferon Γ ◽  
Mononuclear Phagocytes ◽  
Bacterial Lipopolysaccharide ◽  
Interleukin 12 ◽  
Mrna Levels ◽  
Adapter Protein ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Mrna

Abstract In human monocytes and macrophages, interferon-γ (IFNγ) augmented mRNA and surface expression of toll-like receptor 4 (TLR4), a crucial component of the signaling receptor complex for bacterial lipopolysaccharide (LPS). Expression of the accessory component MD-2 and of the adapter protein MyD88 was also increased. LPS increased TLR4 mRNA levels, but concomitantly decreased its surface expression. IFNγ counteracted the LPS-induced downregulation of TLR4. IFNγ-primed monocytes showed increased responsiveness to LPS in terms of phosphorylation of the interleukin-1 receptor–associated kinase (IRAK; immediately downstream of the MyD88 adapter protein), NF-kB DNA binding activity, and, accordingly, of cytokine (tumor necrosis factor α [TNFα] and interleukin-12 [IL-12]) production. These results suggest that enhanced TLR4 expression underlies the long-known priming by IFNγ of mononuclear phagocytes for pathogen recognition and killing as well as its synergism with LPS in macrophage activation.

Atorvastatin suppresses LPS-induced rapid upregulation of Toll-like receptor 4 and its signaling pathway in endothelial cells

2011 ◽  
Vol 300 (5) ◽  
pp. H1743-H1752 ◽  
Author(s):  
Ying Wang ◽  
Ming Xiang Zhang ◽  
Xiao Meng ◽  
Fu Qiang Liu ◽  
Guang Sheng Yu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mrna Expression ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Umbilical Vein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Mapk Phosphorylation ◽  
Tlr4 Mrna

In the present study, we tested our hypothesis that atorvastatin exerts its anti-inflammation effect via suppressing LPS-induced rapid upregulation of Toll-like receptor 4 (TLR4) mRNA and its downstream p38, ERK, and NF-κB signaling pathways in human umbilical-vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs). TLR4 mRNA expression and its downstream kinase activities induced by LPS alone or atorvastatin + LPS in endothelial cells were quantified using quantitative real-time PCR and enzyme-linked immunosorbent assay. Preincubation of LPS-stimulated endothelial cells with TLR4 siRNA was conducted to identify the target of the anti-inflammatory effects of atorvastatin. Atorvastatin incubation resulted in the reduction of LPS-induced TLR4 mRNA expression, ERK1/2 and P38 MAPK phosphorylation, and NF-κB binding activity. Pretreatment with MEK/ERK1/2 inhibitor PD98059 attenuated atorvastatin + LPS-induced NF-κB activity but had no effect on P38 MAPK phosphorylation. In contrast, pretreatment with P38 MAPK inhibitor SB203580 resulted in upregulation of atorvastatin + LPS-induced ERK1/2 phosphorylation but had no significant effects on NF-κB activity. On the other hand, blocking NF-κB with SN50 produced no effects on atorvastatin + LPS-induced ERK1/2 and P38 MAPK phosphorylation. Moreover, TLR4 gene silencing produced the same effects as the atorvastatin treatment. In conclusion, atorvastatin downregulated TLR4 mRNA expression by two distinct signaling pathways. First, atorvastatin stabilized Iκ-Bα, which directly inhibited NF-κB activation. Second, atorvastatin inactivated ERK phosphorylation, which indirectly inhibited NF-κB activation. Suppression of p38 MAPK by atorvastatin upregulates ERK but exerts no effect on NF-κB.

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