scholarly journals Toll-Like Receptor 4 Is an Essential Upstream Regulator of On-Time Parturition and Perinatal Viability in Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3828-3841 ◽  
Author(s):  
Hanan H. Wahid ◽  
Camilla L. Dorian ◽  
Peck Yin Chin ◽  
Mark R. Hutchinson ◽  
Kenner C. Rice ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Preterm Labor ◽  
Late Gestation ◽  
Gestation Length ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
Postterm Pregnancy ◽  
Upstream Regulator

An inflammatory response is instrumental in the physiological process of parturition but the upstream signals initiating inflammation are undefined. Because endogenous ligands for Toll-like receptor 4 (TLR4) are released in late gestation, we hypothesized that on-time labor requires TLR4 signaling, to trigger a cytokine and leukocyte response and accelerate the parturition cascade. In pregnant TLR4-deficient (Tlr4−/−) mice, average gestation length was extended by 13 hours and increased perinatal mortality was seen compared with wild-type controls. Quantification of cytokine and uterine activation gene expression showed that late gestation induction of Il1b, Il6, Il12b, and Tnf expression seen in control placenta and fetal membranes was disrupted in Tlr4−/− mice, and accompanied by a transient delay in expression of uterine activation genes, including prostaglandin F receptor, oxytocin receptor, and connexin-43. Leukocyte populations were altered before birth in TLR4-deficient females, with fewer neutrophils and macrophages in the placenta, and fewer dendritic cells and more regulatory T cells in the myometrium. Administration of TLR4 ligand lipopolysaccharide to pregnant wild-type mice induced cytokine expression and fetal loss, whereas Tlr4−/− pregnancies were protected. The small molecule TLR4 antagonist (+)-naloxone increased mean duration of gestation by 16 hours in wild-type mice. Collectively, these data demonstrate that TLR4 is a key upstream regulator of the inflammatory response acting to drive uterine activation and control the timing of labor. Because causal pathways for term and preterm labor converge with TLR4, interventions to manipulate TLR4 signaling may have therapeutic utility for women at risk of preterm labor, or in postterm pregnancy.

scholarly journals Key Player in Cardiac Hypertrophy, Emphasizing the Role of Toll-Like Receptor 4

2020 ◽  
Vol 7 ◽  
Author(s):  
Zheng Xiao ◽  
Bin Kong ◽  
Hongjie Yang ◽  
Chang Dai ◽  
Jin Fang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cardiac Hypertrophy ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
New Technologies ◽  
Immune Cell ◽  
Current Knowledge ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling

Toll-like receptor 4 (TLR4), a key pattern recognition receptor, initiates the innate immune response and leads to chronic and acute inflammation. In the past decades, accumulating evidence has implicated TLR4-mediated inflammatory response in regulation of myocardium hypertrophic remodeling, indicating that regulation of the TLR4 signaling pathway may be an effective strategy for managing cardiac hypertrophy's pathophysiology. Given TLR4's significance, it is imperative to review the molecular mechanisms and roles underlying TLR4 signaling in cardiac hypertrophy. Here, we comprehensively review the current knowledge of TLR4-mediated inflammatory response and its interaction ligands and co-receptors, as well as activation of various intracellular signaling. We also describe the associated roles in promoting immune cell infiltration and inflammatory mediator secretion, that ultimately cause cardiac hypertrophy. Finally, we provide examples of some of the most promising drugs and new technologies that have the potential to attenuate TLR4-mediated inflammatory response and prevent or reverse the ominous cardiac hypertrophy outcomes.

scholarly journals Ubiquitination of ECSIT is crucial for the activation of p65/p50 NF-κBs in Toll-like receptor 4 signaling

2015 ◽  
Vol 26 (1) ◽  
pp. 151-160 ◽  
Author(s):  
Sae Mi Wi ◽  
Jeongho Park ◽  
Jae-Hyuck Shim ◽  
Eunyoung Chun ◽  
Ki-Young Lee
Keyword(s):  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Tlr Signaling ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
Evolutionarily Conserved ◽  
Biochemical Studies ◽  
Necrosis Factor

Recent evidence shows that evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) interacts with tumor necrosis factor receptor–associated factor 6 (TRAF6), is ubiquitinated, and contributes to bactericidal activity during Toll-like receptor (TLR) signaling. Here we report a new regulatory role for ECSIT in TLR4 signaling. On TLR4 stimulation, endogenous ECSIT formed a molecular complex with p65/p50 NF-κB proteins. Our biochemical studies showed that ECSIT specifically interacted with p65/p50 NF-κB proteins, which colocalized in the nucleus. Of interest, these effects were critically dependent on ubiquitination of the ECSIT lysine (K) 372 residue. K372A mutant ECSIT did not interact with p65/p50 NF-κB proteins and markedly attenuated nuclear colocalization. In addition, ECSIT-knockdown THP-1 cells could not activate NF-κB DNA-binding activities of p65 and p50, production of proinflammatory cytokines, or NF-κB–dependent gene expression in response to TLR4 stimulation. However, these activities were markedly restored by expressing the wild-type ECSIT protein but not the K372A mutant ECSIT protein. These data strongly suggest that the ubiquitination of ECSIT might have a role in the regulation of NF-κB activity in TLR4 signaling.

scholarly journals Toll-like Receptor 4 Signaling in Ventilator-induced Diaphragm Atrophy

2012 ◽  
Vol 117 (2) ◽  
pp. 329-338 ◽  
Author(s):  
Willem-Jan M. Schellekens ◽  
Hieronymus W. H. van Hees ◽  
Michiel Vaneker ◽  
Marianne Linkels ◽  
P. N. Richard Dekhuijzen ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Caspase 3 ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Diaphragm Atrophy ◽  
Deficient Mice

Background Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. Methods Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll-like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. Results Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll-like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll-like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild-type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. Conclusion Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy.

scholarly journals CD4+CD25+Foxp3+ regulatory T cells regulate immune balance in unexplained recurrent spontaneous abortion via the Toll-like receptor 4/nuclear factor-κB pathway

2020 ◽  
Vol 48 (12) ◽  
pp. 030006052098094
Author(s):  
Shuang Qin ◽  
Li Li ◽  
Jia Liu ◽  
Jinrui Zhang ◽  
Qing Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Inflammatory Response ◽  
Mouse Model ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Unexplained Recurrent Spontaneous Abortion ◽  
Tlr4 Antagonist

Objective The present study aimed to evaluate the effects of cluster of differentiation (CD)4+CD25+ forkhead box p3 (Foxp3)+ regulatory T cells (Tregs) on unexplained recurrent spontaneous abortion (URSA) and the associated mechanisms. Methods The proportion of CD4+CD25+Foxp3+ Tregs and inflammatory cytokine concentrations in the peripheral blood of women with URSA were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. CBA/JxDBA/2J mating was used to establish an abortion-prone mouse model and the model mice were treated with the Toll-like receptor 4 (TLR4) antagonist E5564 and the TLR4 agonist lipopolysaccharide. Results The proportion of CD4+CD25+Foxp3+ Tregs was decreased and the inflammatory response was increased in women with URSA. In the abortion-prone mouse model, E5564 significantly increased the proportion of CD4+CD25+Foxp3+ Tregs, decreased the inflammatory response, and increased Foxp3 mRNA and protein expression. Lipopolysaccharide had adverse effects on the abortion-prone model. Conclusions These data suggest that CD4+CD25+Foxp3+ Tregs regulate immune homeostasis in URSA via the TLR4/nuclear factor-κB pathway, and that the TLR4 antagonist E5564 may be a novel and potential drug for treating URSA.

scholarly journals Toll-Like Receptor 4 Signaling and Drug Addiction

2020 ◽  
Vol 11 ◽  
Author(s):  
Ruyan Wu ◽  
Jun-Xu Li
Keyword(s):  
Drug Addiction ◽  
Multiple Drug ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
Drug Classes ◽  
Downstream Effectors ◽  
Potential Efficacy ◽  
Proinflammatory Responses

The emphasis of neuronal alterations and adaptations have long been the main focus of the studies of the mechanistic underpinnings of drug addiction. Recent studies have begun to appreciate the role of innate immune system, especially toll-like receptor 4 (TLR4) signaling in drug reward-associated behaviors and physiology. Drugs like opioids, alcohol and psychostimulants activate TLR4 signaling and subsequently induce proinflammatory responses, which in turn contributes to the development of drug addiction. Inhibition of TLR4 or its downstream effectors attenuated the reinforcing effects of opioids, alcohol and psychostimulants, and this effect is also involved in the withdrawal and relapse-like behaviors of different drug classes. However, conflicting results also argue that TLR4-related immune response may play a minimal part in drug addiction. This review discussed the preclinical evidence that whether TLR4 signaling is involved in multiple drug classes action and the possible mechanisms underlying this effect. Moreover, clinical studies which examined the potential efficacy of immune-base pharmacotherapies in treating drug addiction are also discussed.

Monosodium urate crystal interleukin-1β release is dependent on Toll-like receptor 4 and transient receptor potential V1 activation

Rheumatology ◽  
2019 ◽  
Author(s):  
Mateus F. Rossato ◽  
Carin Hoffmeister ◽  
Gabriela Trevisan ◽  
Fabio Bezerra ◽  
Thiago M. Cunha ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Synovial Fluid ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Acute Gout ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Transient Receptor ◽  
Nitrite Nitrate

AbstractObjectiveThe present study aimed to elucidate the mechanisms involved in MSU-induced IL-1β release in a rodent animal model of acute gout arthritis.MethodsPainful (mechanical and thermal hypersensitivity, ongoing pain and arthritis score) and inflammatory (oedema, plasma extravasation, cell infiltration and IL-1β release) parameters were assessed several hours after intra-articular injection of MSU (100 µg/articulation) in wild-type or knockout mice for Toll-like receptor 4 (TLR4), inducible nitric oxide synthase (iNOS), transient receptor potential (TRP) V1 and the IL-1 receptor (IL-1R). Also, wild-type animals were treated with clodronate, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) (TLR4 antagonist), spleen tyrosine kinase (SYK) inhibitor (iSYK), aminoguanidine (AMG, an iNOS inhibitor) or SB366791 (TRPV1 antagonist). Nitrite/nitrate and IL-1β levels were measured on the synovial fluid of wild-type mice, 2 h after intra-articular MSU injections, or medium from macrophages stimulated for MSU (1000 μg) for 2 h.ResultsIntra-articular MSU injection caused robust nociception and severe inflammation from 2 up to 6 h after injection, which were prevented by the pre-treatment with clodronate, LPS-RS, iSYK, AMG and SB366791, or the genetic ablation of TLR4, iNOS, TRPV1 or IL-1R. MSU also increased nitrite/nitrate and IL-1β levels in the synovial fluid, which was prevented by clodronate, LPS-RS, iSYK and AMG, but not by SB366791. Similarly, MSU-stimulated peritoneal macrophages released nitric oxide, which was prevented by LPS-RS, iSYK and AMG, but not by SB366791, and released IL-1β, which was prevented by LPS-RS, iSYK, AMG and SB366791.ConclusionOur data indicate that MSU may activate TLR4, SYK, iNOS and TRPV1 to induce the release of IL-1β by macrophages, triggering nociception and inflammation during acute gout attack.

scholarly journals Immunomodulatory Effects of Yersinia pestis Lipopolysaccharides on Human Macrophages

2009 ◽  
Vol 17 (1) ◽  
pp. 49-55 ◽  
Author(s):  
Motohiro Matsuura ◽  
Hideyuki Takahashi ◽  
Haruo Watanabe ◽  
Shinji Saito ◽  
Kazuyoshi Kawahara
Keyword(s):  
Inflammatory Response ◽  
Yersinia Pestis ◽  
Lipid A ◽  
Antagonistic Activity ◽  
Gram Negative Bacteria ◽  
Toll Like Receptor ◽  
Defense System ◽  
Toll Like Receptor 4 ◽  
Bacterial Binding ◽  
Binding Forms

ABSTRACTIn the current study, we investigated the activity of lipopolysaccharide (LPS) purified fromYersinia pestisgrown at either 27°C or 37°C (termed LPS-27 and LPS-37, respectively). LPS-27 containing hexa-acylated lipid A, similar to the LPS present in usual gram-negative bacteria, stimulated an inflammatory response in human U937 cells through Toll-like receptor 4 (TLR4). LPS-37, which did not contain hexa-acylated lipid A, exhibited strong antagonistic activity to the TLR4-mediated inflammatory response. The phagocytic activity in the cells was not affected by LPS-37. To estimate the activity of LPS in its bacterial binding form, formalin-killed bacteria (FKB) were prepared fromY. pestiscells grown at 27°C or 37°C (termed FKB-27 and FKB-37, respectively). FKB-27 strongly stimulated the inflammatory response. This activity was suppressed in the presence of an anti-TLR4 antibody but not an anti-TLR2 antibody. In addition, this activity was almost completely suppressed by LPS-37, indicating that the activity of FKB-27 is predominantly derived from the LPS-27 bacterial binding form. In contrast, FKB-37 showed no antagonistic activity. The results arising from the current study indicate thatY. pestiscauses infection in humans without stimulating the TLR4-based defense systemviabacterial binding of LPS-37, even when bacterial free LPS-37 is not released to suppress the defense system. This is in contrast to the findings for bacteria that possess agonistic LPS types, which are easily recognized by the defense systemviathe bacterial binding forms.

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