A Novel Cyclohexene Derivative, Ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), Selectively Inhibits Toll-Like Receptor 4-Mediated Cytokine Production through Suppression of Intracellular Signaling

2005 ◽  
Vol 69 (4) ◽  
pp. 1288-1295 ◽  
Author(s):  
Masayuki Ii ◽  
Naoko Matsunaga ◽  
Kaoru Hazeki ◽  
Kazuyo Nakamura ◽  
Katsunori Takashima ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Cytokine Production ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

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 Bacteroides fragilis-Derived Lipopolysaccharide Produces Cell Activation and Lethal Toxicity via Toll-Like Receptor 4

2005 ◽  
Vol 73 (9) ◽  
pp. 5620-5627 ◽  
Author(s):  
Giuseppe Mancuso ◽  
Angelina Midiri ◽  
Carmelo Biondo ◽  
Concetta Beninati ◽  
Maria Gambuzza ◽  
...  
Keyword(s):  
Cell Activation ◽  
Cytokine Production ◽  
Biological Activities ◽  
Endotoxic Shock ◽  
Intestinal Flora ◽  
Bacteroides Fragilis ◽  
Peritoneal Macrophages ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
In Cells

ABSTRACT Bacteroides fragilis, which is part of the normal intestinal flora, is a frequent cause of serious disease, especially in diabetic and surgical patients. In these conditions, B. fragilis lipopolysaccharide (LPS) is likely to play a major pathophysiologic role. B. fragilis LPS is structurally different from classical enterobacterial LPS, whose biological activities are mediated by Toll-like receptor 4 (TLR4) activation. The ability of B. fragilis LPS to activate TLR4 and TLR2 was investigated here, since evidence on this issue is scarce and controversial. Each of four different protein-free B. fragilis LPS preparations could induce interleukin-8 responses in cells cotransfected with TLR4/CD14/MD2 but not TLR4/CD14 alone. Two of the preparations also induced cytokine production in cells cotransfected with TLR2/CD14 or in peritoneal macrophages from TLR4 mutant C3H/HeJ mice. Both of these activities, however, were lost after repurification with a modified phenol reextraction procedure. Importantly, all preparations could induce endotoxic shock in TLR2-deficient mice, but not in TLR4 mutant C3H/HeJ mice. Consistent with these findings, anti-TLR4 and anti-CD14, but not anti-TLR2, antibodies could inhibit B. fragilis LPS-induced cytokine production in human monocytes. Collectively, these results indicate that B. fragilis LPS signals via a TLR4/CD14/MD2-dependent pathway, and it is unable to activate TLR2. Moreover, our data document the occurrence of TLR2-activating contaminants even in highly purified B. fragilis LPS preparations. This may explain earlier contradictory findings on the ability of B. fragilis LPS to activate cells in the absence of functional TLR4. These data may be useful to devise strategies to prevent the pathophysiologic changes observed during B. fragilis sepsis and to better understand structure-activity relationships of LPS.

scholarly journals Activation of Porcine Alveolar Macrophages byActinobacillus pleuropneumoniaeLipopolysaccharide via the Toll-Like Receptor 4/NF-κB-Mediated Pathway

2017 ◽  
Vol 86 (3) ◽  
Author(s):  
Bi Li ◽  
Jing Fang ◽  
Zhicai Zuo ◽  
Sirui Yin ◽  
Tingting He ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Alveolar Macrophages ◽  
Intracellular Signaling ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Immunological Responses ◽  
Pathogen Invasion ◽  
Porcine Contagious Pleuropneumonia

ABSTRACTActinobacillus pleuropneumoniaeis the causative agent of porcine contagious pleuropneumonia. Overproduction of proinflammatory cytokines, like interleukin-1β (IL-1β), IL-6, tumor necrosis factor alpha, and resistin, in the lung is an important feature ofA. pleuropneumoniaeinfection. These proinflammatory cytokines enhance inflammatory and immunological responses. However, the mechanism that leads to cytokine production remains unclear. As a major virulence factor ofA. pleuropneumoniae, lipopolysaccharide (LPS) may act as a potent stimulator of Toll-like receptor 4 (TLR4), triggering a number of intracellular signaling pathways that lead to the synthesis of proinflammatory cytokines. Porcine alveolar macrophages (PAMs) are the first line of defense against pathogenic microbes during pathogen invasion. The results of the present study demonstrate thatA. pleuropneumoniaeLPS induces PAMs to produce inflammatory cytokines in time- and dose-dependent manners. Moreover, PAMs were activated byA. pleuropneumoniaeLPS, resulting in upregulation of signaling molecules, including TLR4, MyD88, TRIF-related adaptor molecule, and NF-κB. In contrast, the activation effects ofA. pleuropneumoniaeLPS on PAMs could be suppressed by specific inhibitors, like small interfering RNA and Bay11-7082. Taken together, our data indicate thatA. pleuropneumoniaeLPS can induce PAMs to produce proinflammatory cytokines via the TLR4/NF-κB-mediated pathway. These findings partially reveal the mechanism of the overproduction of proinflammatory cytokines in the lungs of swine withA. pleuropneumoniaeinfection and may provide targets for the prevention ofA. pleuropneumoniae-induced pneumonia. All the data could be used as a reference for the pathogenesis of respiratory infection.

Safflower polysaccharides activate the transcription factor NF-κB via Toll-like receptor 4 and induce cytokine production by macrophages

2002 ◽  
Vol 2 (8) ◽  
pp. 1155-1162 ◽  
Author(s):  
Izuru Ando ◽  
Yoshinori Tsukumo ◽  
Tetsuya Wakabayashi ◽  
Sachiko Akashi ◽  
Kensuke Miyake ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cytokine Production ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

OR.44. Toll-like Receptor 4 Engagement Blocks Inflammatory Cytokine Production by B Cells from Inflammatory Disease Patients

2009 ◽  
Vol 131 ◽  
pp. S21
Author(s):  
Madhumita Jagannathan ◽  
Hyunjin Shin ◽  
Yue Zhang ◽  
Hatice Hasturk ◽  
Alpdogan Kantarci ◽  
...  
Keyword(s):  
B Cells ◽  
Inflammatory Disease ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Inflammatory Cytokine Production
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