Lipopolysaccharide-induced inhibition of transcription of tlr4 in vitro is reversed by dexamethasone and correlates with presence of conserved NFκB binding sites

Bonin, Camila P.; Baccarin, Raquel Yvonne Arantes; Nostell, Katarina; Nahum, Laila Alves; Fossum, Caroline; Camargo, Maristela Martins de

doi:10.1016/j.bbrc.2013.02.002

Cited by 13 publications

(7 citation statements)

References 31 publications

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“…Moreover, the NF‐κB signal pathway which was correlated with inflammatory response is significantly enriched by the GO analysis. Studies have identified that NF‐κB could bind to TLR4 and NLRP3 promoter region, suggesting the transcriptional regulation of NF‐κB on TLR4 and NLRP3 and its downstream targets . Furthermore, melatonin could suppress NF‐κB‐dependent pro‐inflammatory mediators in various cell types .…”

Section: Discussionmentioning

confidence: 99%

Melatonin alleviates inflammasome‐induced pyroptosis through inhibiting NF‐κB/GSDMD signal in mice adipose tissue

Liu

Gan

et al. 2017

Journal of Pineal Research

309

244

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Pyroptosis is a proinflammatory form of cell death that is associated with pathogenesis of many chronic inflammatory diseases. Melatonin is substantially reported to possess anti-inflammatory properties by inhibiting inflammasome activation. However, the effects of melatonin on inflammasome-induced pyroptosis in adipocytes remain elusive. Here, we demonstrated that melatonin alleviated lipopolysaccharides (LPS)-induced inflammation and NLRP3 inflammasome formation in mice adipose tissue. The NLRP3 inflammasome-mediated pyroptosis was also inhibited by melatonin in adipocytes. Further analysis revealed that gasdermin D (GSDMD), the key executioner of pyroptosis, was the target for melatonin inhibition of adipocyte pyroptosis. Importantly, we determined that nuclear factor κB (NF-κB) signal was required for the GSDMD-mediated pyroptosis in adipocytes. We also confirmed that melatonin alleviated adipocyte pyroptosis by transcriptional suppression of GSDMD. Moreover, GSDMD physically interacted with interferon regulatory factor 7 (IRF7) and subsequently formed a complex to promote adipocyte pyroptosis. Melatonin also attenuated NLRP3 inflammasome activation and pyroptosis, which was induced by LPS or obesity. In summary, our results demonstrate that melatonin alleviates inflammasome-induced pyroptosis by blocking NF-κB/GSDMD signal in mice adipose tissue. Our data reveal a novel function of melatonin on adipocyte pyroptosis, suggesting a new potential therapy for melatonin to prevent and treat obesity caused systemic inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Melatonin alleviates inflammasome‐induced pyroptosis through inhibiting NF‐κB/GSDMD signal in mice adipose tissue

Liu

Gan

et al. 2017

Journal of Pineal Research

309

244

View full text Add to dashboard Cite

show abstract

“…Inflammasome, a group of protein complexes, functions as a sensor to detect danger signals and induces secretion of potent pro-inflammatory cytokines that contribute to obesity-associated chronic inflammation conditions ( 3 , 39 , 40 ). The NF-κB signal pathway which was correlated with inflammatory response and has been identified binding to NLRP3 promoter and transcriptional regulating NLRP3 and its downstream targets ( 41 , 42 ). In this study, we determined that Hoxa5 may take part in the regulation of NLRP3 inflammasome by modulating the NF-κB signal in adipocytes.…”

Section: Discussionmentioning

confidence: 99%

Homeobox a5 Promotes White Adipose Tissue Browning Through Inhibition of the Tenascin C/Toll-Like Receptor 4/Nuclear Factor Kappa B Inflammatory Signaling in Mice

et al. 2018

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Lipopolysaccharide (LPS) induces rapid increase in systemic inflammatory factors. As adipose tissue is a key contributor to the inflammatory response to numerous metabolic stimuli, it is important to understand the mechanism behind the LPS-induced inflammation in white adipose tissue (WAT). Homeobox a5 (Hoxa5) is an important transcription factor, which is highly expressed in adipose tissue, and its mRNA expression is increased at cold exposure in mice. So far, the function of Hoxa5 in adipose tissue browning has been poorly understood. So, the objective of this study was conducted to determine the role of Hoxa5 in adipose inflammatory response and white adipose browning in mice. LPS-induced inflammatory and cold-induced browning model were conducted. We compared the coordinated role of Hoxa5 in inflammation and thermogenesis of mice adipose. Transcriptional and methylation regulation was determined by luciferase assay, electrophoretic mobility shift assay, and bisulfite conversion experiment. Hoxa5 and tenascin C (TNC) were involved in WAT inflammation and browning in mice with LPS injection. Furthermore, Hoxa5 inhibited the TNC-involved activation of Toll-like receptor (TLR) 4/nuclear factor kappa B (NF-κB) signal pathway and promoted WAT browning. Moreover, we found that a BMP4/Smad1 signal, closely related to browning, was activated by Hoxa5. Hoxa5 relieved adipocyte inflammation by decreasing TNC-mediated TLR4 transducer and activator of the NF-κB pathway. Interestingly, descended methylation level increased Hoxa5 expression in cold exposure. Our findings demonstrated that Hoxa5 alleviated inflammation and enhanced browning of adipose tissue via negative control of TNC/TLR4/NF-κB inflammatory signaling and activating BMP4/Smad1 pathway. These findings indicated a novel potential means for the regulation of inflammation in adipocytes to prevent obesity and other inflammatory diseases.

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“…LPS and GCs trigger different, sometimes opposite, signaling pathways. Activated GR interferes with the transcriptional activation function of nuclear factor kappa b (NFkB) 36 , while LPS induces the phosphorylation and translocation of NFkB to the nucleus 37 . GCs activate a phosphatase, responsible for the de-activation of mitogen activated protein kinase (MAPK) pathway 38 while LPS activates the MAPK pathway 39 .…”

Section: Discussionmentioning

confidence: 99%

Resistance of LPS-activated bone marrow derived macrophages to apoptosis mediated by dexamethasone

Haim

Unger

Souroujon

et al. 2014

Sci Rep

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Glucocorticoids (GC) display pleiotropic effects on the immune system. Macrophages are a major target for GC action. Here we show that dexamethasone (DEX), a synthetic GC, decreased viability of naïve bone marrow-derived macrophages (BMDM), involving an apoptotic mechanism. Administration of DEX together with lipopolysaccharide (LPS) protected BMDM against DEX-mediated cell death, suggesting that activated BMDM respond to DEX differently than naïve BMDM. An insight to the molecular basis of LPS actions was provided by a 7 fold increase in mRNA levels of glucocorticoid receptor beta (GRβ), a GR dominant-negative splice variant which inhibits GRα's transcriptional activity. LPS did not inhibit all DEX-mediated effects on BMDM; DEX significantly reduced the percentage of BMDM expressing high levels of the cell surface markers F4/80 and CD11b and led to a decrease in macrophage inflammatory protein 1 alpha (MIP1-α) mRNA and protein levels. These two DEX-mediated effects were not prevented by LPS. Our finding that LPS did not reduce the DEX-induced elevation of glucocorticoid-induced leucine zipper (GILZ), a mediator of GCs anti-inflammatory actions, may provide an underlying mechanism. These findings enable a better understanding of clinical states, such as sepsis, in which macrophages are activated by endotoxins and treatment by GCs is considered.

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Lipopolysaccharide-induced inhibition of transcription of tlr4 in vitro is reversed by dexamethasone and correlates with presence of conserved NFκB binding sites

Cited by 13 publications

References 31 publications

Melatonin alleviates inflammasome‐induced pyroptosis through inhibiting NF‐κB/GSDMD signal in mice adipose tissue

Melatonin alleviates inflammasome‐induced pyroptosis through inhibiting NF‐κB/GSDMD signal in mice adipose tissue

Homeobox a5 Promotes White Adipose Tissue Browning Through Inhibition of the Tenascin C/Toll-Like Receptor 4/Nuclear Factor Kappa B Inflammatory Signaling in Mice

Resistance of LPS-activated bone marrow derived macrophages to apoptosis mediated by dexamethasone

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