Signaling for myocardial depression in hemorrhagic shock: roles of Toll-like receptor 4 and p55 TNF-α receptor

Hemorrhagic shock causes myocardial contractile depression. Although this myocardial disorder is associated with increased expression of tumor necrosis factor-α (TNF-α), the role of TNF-α as a myocardial depressant factor in hemorrhagic shock remains to be determined. Moreover, it is unclear which TNF-α receptor mediates the myocardial depressive effects of TNF-α. Toll-like receptor 4 (TLR4) regulates cellular expression of proinflammatory mediators following lipopolysaccharide stimulation and may be involved in the tissue inflammatory response to injury. The contribution of TLR4 signaling to tissue TNF-α response to hemorrhagic shock and TLR4’s role in myocardial depression during hemorrhagic shock are presently unknown. We examined the relationship of TNF-α production to myocardial depression in a mouse model of nonresuscitated hemorrhagic shock, assessed the influence of TLR4 mutation, resulting in defective signaling, on TNF-α production and myocardial depression, and determined the roles of TNF-α and TNF-α receptors in myocardial depression using a gene knockout (KO) approach. Hemorrhagic shock resulted in increased plasma and myocardial TNF-α (4.9- and 4.5-fold, respectively) at 30 min and induced myocardial contractile depression at 4 h. TLR4 mutation abolished the TNF-α response and attenuated myocardial depression (left ventricular developed pressure of 43.0 ± 6.2 mmHg in TLR4 mutant vs. 30.0 ± 3.6 mmHg in wild type, P < 0.05). TNF-α KO also attenuated myocardial depression in hemorrhagic shock, and the p55 receptor KO, but not the p75 receptor KO, mimicked the effect of TNF-α KO. The results suggest that TLR4 plays a novel role in signaling to the TNF-α response during hemorrhagic shock and that TNF-α through the p55 receptor activates a pathway leading to myocardial depression. Thus TLR4 and the p55 TNF-α receptor represent therapeutic targets for preservation of cardiac mechanical function during hemorrhagic shock.

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Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome

European Heart Journal ◽

10.1093/eurheartj/ehaa973 ◽

2020 ◽

Author(s):

Andrea Frustaci ◽

Maria Alfarano ◽

Romina Verardo ◽

Chiara Agrati ◽

Rita Casetti ◽

...

Keyword(s):

Hospital Mortality ◽

Hypereosinophilic Syndrome ◽

Left Ventricular ◽

Response To Therapy ◽

Left Ventricular Ejection ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Ventricular Ejection Fraction ◽

Immune Mediated ◽

Coronary Vasculitis

Abstract Aims Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported. Methods and results Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients. Conclusion Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression.

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Differential Induction of the Toll-Like Receptor 4-MyD88-Dependent and -Independent Signaling Pathways by Endotoxins

Infection and Immunity ◽

10.1128/iai.73.5.2940-2950.2005 ◽

2005 ◽

Vol 73 (5) ◽

pp. 2940-2950 ◽

Cited By ~ 131

Author(s):

Susu M. Zughaier ◽

Shanta M. Zimmer ◽

Anup Datta ◽

Russell W. Carlson ◽

David S. Stephens

Keyword(s):

Nitric Oxide ◽

Signaling Pathways ◽

Lipid A ◽

Raw 264.7 ◽

Receptor Complex ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Nitric Oxide Release ◽

Tnf Α ◽

Dependent Pathway

ABSTRACT The biological response to endotoxin mediated through the Toll-like receptor 4 (TLR4)-MD-2 receptor complex is directly related to lipid A structure or configuration. Endotoxin structure may also influence activation of the MyD88-dependent and -independent signaling pathways of TLR4. To address this possibility, human macrophage-like cell lines (THP-1, U937, and MM6) or murine macrophage RAW 264.7 cells were stimulated with picomolar concentrations of highly purified endotoxins. Harvested supernatants from previously stimulated cells were also used to stimulate RAW 264.7 or 23ScCr (TLR4-deficient) macrophages (i.e., indirect induction). Neisseria meningitidis lipooligosaccharide (LOS) was a potent direct inducer of the MyD88-dependent pathway molecules tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 3α (MIP-3α), and the MyD88-independent molecules beta interferon (IFN-β), nitric oxide, and IFN-γ-inducible protein 10 (IP-10). Escherichia coli 55:B5 and Vibrio cholerae lipopolysaccharides (LPSs) at the same pmole/ml lipid A concentrations induced comparable levels of TNF-α, IL-1β, and MIP-3α, but significantly less IFN-β, nitric oxide, and IP-10. In contrast, LPS from Salmonella enterica serovars Minnesota and Typhimurium induced amounts of IFN-β, nitric oxide, and IP-10 similar to meningococcal LOS but much less TNF-α and MIP-3α in time course and dose-response experiments. No MyD88-dependent or -independent response to endotoxin was seen in TLR4-deficient cell lines (C3H/HeJ and 23ScCr) and response was restored in TLR4-MD-2-transfected human embryonic kidney 293 cells. Blocking the MyD88-dependent pathway by DNMyD88 resulted in significant reduction of TNF-α release but did not influence nitric oxide release. IFN-β polyclonal antibody and IFN-α/β receptor 1 antibody significantly reduced nitric oxide release. N. meningitidis endotoxin was a potent agonist of both the MyD88-dependent and -independent signaling pathways of the TLR4 receptor complex of human macrophages. E. coli 55:B5 and Vibrio cholerae LPS, at the same picomolar lipid A concentrations, selectively induced the MyD88-dependent pathway, while Salmonella LPS activated the MyD88-independent pathway.

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Partially Silencing Brain Toll-Like Receptor 4 Prevents in Part Left Ventricular Remodeling with Sympathoinhibition in Rats with Myocardial Infarction-Induced Heart Failure

PLoS ONE ◽

10.1371/journal.pone.0069053 ◽

2013 ◽

Vol 8 (7) ◽

pp. e69053 ◽

Cited By ~ 9

Author(s):

Kiyohiro Ogawa ◽

Yoshitaka Hirooka ◽

Takuya Kishi ◽

Tomomi Ide ◽

Kenji Sunagawa

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Left Ventricular ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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TNF-α Activates High-Mobility Group Box 1 - Toll-Like Receptor 4 Signaling Pathway in Human Aortic Endothelial Cells

Cellular Physiology and Biochemistry ◽

10.1159/000445570 ◽

2016 ◽

Vol 38 (6) ◽

pp. 2139-2151 ◽

Cited By ~ 16

Author(s):

Won Seok Yang ◽

Nam Jeong Han ◽

Jin Ju Kim ◽

Mee Jeong Lee ◽

Su-Kil Park

Keyword(s):

Signal Transduction ◽

Endothelial Cells ◽

High Mobility ◽

Neutralizing Antibody ◽

High Mobility Group ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Aortic Endothelial Cells ◽

Tnf Α ◽

Human Aortic Endothelial Cells

Background/Aims: Toll-like receptor 4 (TLR4) interacts with endogenous substances as well as lipopolysaccharide. We explored whether TLR4 is implicated in tumor necrosis factor-α (TNF-α) signal transduction in human aortic endothelial cells. Methods: The pathway was evaluated by transfection of siRNAs, immunoprecipitation and Western blot analysis. Results: TNF-α activated spleen tyrosine kinase (Syk) within 10 min, which led to endothelin-1 (ET-1) production. TLR4 was also rapidly activated by TNF-α stimulation, as shown by recruitment of interleukin-1 receptor-associated kinase 1 to TLR4 and its adaptor molecule, myeloid differentiation factor 88 (MyD88). siRNA depletion of TLR4 markedly attenuated TNF-α-induced Syk activation and ET-1 production. TLR4 inhibitor (CLI-095), TLR4-neutralizing antibody and siRNA depletion of MyD88 also attenuated TNF-α-induced Syk activation. Syk was co-immunoprecipitated with TLR4, and TNF-α activated Syk bound to TLR4. High-mobility group box 1 (HMGB1) was rapidly released and associated with TLR4 after TNF-α stimulation with a peak at 5 min, which was prevented by N-acetylcysteine, an antioxidant. Glycyrrhizin (HMGB1 inhibitor), HMGB1-neutralizing antibody and siRNA depletion of HMGB1 all suppressed TNF-α-induced Syk activation and ET-1 production. Conclusion: Upon TNF-α stimulation, TLR4 is activated by HMGB1 that is immediately released after the generation of reactive oxygen species, and plays a crucial role in the signal transduction.

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Oxymatrine inhibits lipopolysaccharide-induced inflammation by down-regulating Toll-like receptor 4/nuclear factor-kappa B in macrophages

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2014-0362 ◽

2015 ◽

Vol 93 (4) ◽

pp. 253-260 ◽

Cited By ~ 22

Author(s):

Yu Zhang ◽

Ruhong Yan ◽

Yae Hu

Keyword(s):

Nitric Oxide ◽

Interleukin 1 ◽

Chinese Herb ◽

Mrna Levels ◽

Nuclear Factor ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Anti Inflammatory

Oxymatrine (OMT) is the quinolizidine alkaloid extracted from the Chinese herb Sophora flavescens Ait. that has many pharmacological effects and is used for the treatment of some inflammatory diseases. In this study, RAW264.7 cells and THP-1 differentiated macrophages were pretreated with various concentrations of OMT at 2 h prior to treatment with lipopolysaccharide (LPS) (1.0 μg/mL) for different durations. We detected the anti-inflammatory effect of OMT in LPS-stimulated macrophages and investigated the molecular mechanism. We showed that OMT pretreatment significantly inhibited the LPS-induced secretion of nitric oxide (NO), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) in supernatant, attenuated the mRNA levels of inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, and Toll-like receptor 4 (TLR4), increased TLR4 and phosphorylation of inhibitor of kappa B-alpha (p-IBα) in cytosol, and decreased the nuclear level of nuclear factor-κB (NF-κB) p65 in macrophages. In conclusion, OMT exerts anti-inflammatory properties in LPS-stimulated macrophages by down-regulating the TLR4/NF-κB pathway.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.2.r502 ◽

1998 ◽

Vol 275 (2) ◽

pp. R502-R508 ◽

Cited By ~ 13

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.

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

Journal of Applied Physiology ◽

10.1152/japplphysiol.00359.2003 ◽

2003 ◽

Vol 95 (5) ◽

pp. 1833-1842 ◽

Cited By ~ 72

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.

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Micrococcus luteus Teichuronic Acids Activate Human and Murine Monocytic Cells in a CD14- and Toll-Like Receptor 4-Dependent Manner

Infection and Immunity ◽

10.1128/iai.69.4.2025-2030.2001 ◽

2001 ◽

Vol 69 (4) ◽

pp. 2025-2030 ◽

Cited By ~ 32

Author(s):

Shuhua Yang ◽

Shunji Sugawara ◽

Toshihiko Monodane ◽

Masahiro Nishijima ◽

Yoshiyuki Adachi ◽

...

Keyword(s):

Lipid A ◽

Micrococcus Luteus ◽

Dependent Manner ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Necrosis Factor Alpha ◽

Monocytic Cells ◽

Tnf Α

ABSTRACT Teichuronic acid (TUA), a component of the cell walls of the gram-positive organism Micrococcus luteus (formerlyMicrococcus lysodeikticus), induced inflammatory cytokines in C3H/HeN mice but not in lipopolysaccharide (LPS)-resistant C3H/HeJ mice that have a defect in the Toll-like receptor 4 (TLR4) gene, both in vivo and in vitro, similarly to LPS (T. Monodane, Y. Kawabata, S. Yang, S. Hase, and H. Takada, J. Med. Microbiol. 50:4–12, 2001). In this study, we found that purified TUA (p-TUA) induced tumor necrosis factor alpha (TNF-α) in murine monocytic J774.1 cells but not in mutant LR-9 cells expressing membrane CD14 at a lower level than the parent J774.1 cells. The TNF-α-inducing activity of p-TUA in J774.1 cells was completely inhibited by anti-mouse CD14 monoclonal antibody (MAb). p-TUA also induced interleukin-8 (IL-8) in human monocytic THP-1 cells differentiated to macrophage-like cells expressing CD14. Anti-human CD14 MAb, anti-human TLR4 MAb, and synthetic lipid A precursor IVA, an LPS antagonist, almost completely inhibited the IL-8-inducing ability of p-TUA, as well as LPS, in the differentiated THP-1 cells. Reduced p-TUA did not exhibit any activities in J774.1 or THP-1 cells. These findings strongly suggested that M. luteus TUA activates murine and human monocytic cells in a CD14- and TLR4-dependent manner, similar to LPS.

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