BAY 11-7082 Is a Broad-Spectrum Inhibitor with Anti-Inflammatory Activity against Multiple Targets

Lee, Jaehwi; Rhee, Man Hee; Kim, Eunji; Cho, Jae Youl

doi:10.1155/2012/416036

Cited by 132 publications

(99 citation statements)

References 41 publications

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“…To confirm the above observation that EA rescues hyperoxia-compromised macrophage functions via inhibiting HMGB1 release by attenuating NF-kB activation, BAY 11-7082, a well known NF-kB inhibitor (44), was used in the following experiment. Whereas the p65 subunit of NF-kB was primarily observed in the nuclei of RAW 264.7 cells exposed to 95% O 2 in the absence of BAY 11-7082 ( Figure 6A), it was mainly localized in the cytoplasm of RAW 264.7 cells incubated with 1 mM of BAY 11-7082 ( Figure 6A).…”

Section: Ea Suppresses Nf-kb Activationmentioning

confidence: 90%

The Compromise of Macrophage Functions by Hyperoxia Is Attenuated by Ethacrynic Acid via Inhibition of NF-κB–Mediated Release of High-Mobility Group Box-1

Wang

Gorasiya

Antoine

et al. 2015

Am J Respir Cell Mol Biol

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The prolonged exposure to hyperoxia can compromise macrophage functions and contribute to the development of ventilator-associated pneumonia. High levels of extracellular high-mobility group box-1 (HMGB1) in the airways of mice exposed to hyperoxia can directly cause macrophage dysfunction. Hence, inhibition of the release of nuclear HMGB1 into the extracellular milieu may help to maintain macrophage functions under hyperoxic conditions. The present study investigates whether ethacrynic acid (EA) affects hyperoxiainduced HMGB1 release from macrophages and improves their functions. Macrophage-like RAW 264.7 cells and bone marrowderived macrophages were exposed to different concentrations of EA for 24 hours in the presence of 95% O 2 . EA significantly decreased the accumulation of extracellular HMGB1 in cultured media. Importantly, the phagocytic activity and migration capability of macrophages were significantly enhanced in EA-treated cells. Interestingly, hyperoxia-induced NF-kB activation was also inhibited in these cells. To determine whether NF-kB plays a role in hyperoxia-induced HMGB1 release, BAY 11-7082, an inhibitor of NF-kB activation, was used. Similar to EA, BAY 11-7082 significantly inhibited the accumulation of extracellular HMGB1 and improved hyperoxia-compromised macrophage migration and phagocytic activity. Furthermore, 24-hour hyperoxic exposure of macrophages caused hyperacetylation of HMGB1 and its subsequent cytoplasmic translocation and release, which were inhibited by EA and BAY 11-7082. Together, these results suggest that EA enhances hyperoxia-compromised macrophage functions by inhibiting HMGB1 hyperacetylation and its release from macrophages, possibly through attenuation of the NF-kB activation. Therefore, the activation of NF-kB could be one of the underlying mechanisms that mediate hyperoxia-compromised macrophage functions.Keywords: hyperoxia; macrophage; high-mobility group box-1; phagocytosis; NF-kB Clinical RelevanceWe demonstrate that modulating extracellular levels of highmobility group box-1 by inhibitors to NF-kB activation could be used as a potential approach to improve hyperoxiacompromised macrophage functions. If these results can be translated to humans, it is possible that ethacrynic acid could be used as part of the treatment for patients with ventilatorassociated pneumonia.

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Section: Ea Suppresses Nf-kb Activationmentioning

confidence: 90%

The Compromise of Macrophage Functions by Hyperoxia Is Attenuated by Ethacrynic Acid via Inhibition of NF-κB–Mediated Release of High-Mobility Group Box-1

Wang

Gorasiya

Antoine

et al. 2015

Am J Respir Cell Mol Biol

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“…Both compounds, however, have been shown to directly or indirectly modulate numerous cellular targets, including JAK kinase, ERK, and JNK (58,59). Interestingly, celastrol was recently shown to act on activation of the kinase SYK, a very early signaling event during NET formation in response to serum IgG from SLE and RA patients (60).…”

Section: Discussionmentioning

confidence: 99%

Signal Inhibitory Receptor on Leukocytes-1 Limits the Formation of Neutrophil Extracellular Traps, but Preserves Intracellular Bacterial Killing

Avondt

Linden

Naccache

et al. 2016

The Journal of Immunology

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In response to microbial invasion, neutrophils release neutrophil extracellular traps (NETs) to trap and kill extracellular microbes. Alternatively, NET formation can result in tissue damage in inflammatory conditions and may perpetuate autoimmune disease. Intervention strategies that are aimed at modifying pathogenic NET formation should ideally preserve other neutrophil antimicrobial functions. We now show that signal inhibitory receptor on leukocytes-1 (SIRL-1) attenuates NET release by human neutrophils in response to distinct triggers, including opsonized Staphylococcus aureus and inflammatory danger signals. NET release has different kinetics depending on the stimulus, and rapid NET formation is independent of NADPH oxidase activity. In line with this, we show that NET release and reactive oxygen species production upon challenge with opsonized S. aureus require different signaling events. Importantly, engagement of SIRL-1 does not affect bacterially induced production of reactive oxygen species, and intracellular bacterial killing by neutrophils remains intact. Thus, our studies define SIRL-1 as an intervention point of benefit to suppress NET formation in disease while preserving intracellular antimicrobial defense.

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“…Thus, based on the considerable qualitative and quantitative similarities between the pharmacological effects elicited by BAY 11-7082 and the NLRP3 gene silencing in our experimental conditions, we speculate that of NLRP3 inflammasome-dependent cellular and molecular events mediating the protective effects of BAY 11-7082 against diet-induced metabolic abnormalities. It has to be stressed, however, that BAY 11-7082 is not only an inhibitor of NLRP3 inflammasome activity, since this molecule may act also as an inhibitor of NF-κB activation and other inflammatory signaling pathways (42). For this reason, we also investigated the effects of BAY 11-7082 on NF-κB nuclear translocation, since BAY 11-7082 is known to block IκBα phosphorylation and the subsequent NF-κB activation, independently of its inhibitory effects on NLRP3 inflammasome formation and activation (24).…”

Section: Discussionmentioning

confidence: 99%

Targeting the NLRP3 inflammasome to Reduce Diet-induced Metabolic Abnormalities in Mice

Chiazza

Couturier-Maillard

Benetti

et al. 2015

Mol Med

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Although the molecular links underlying the causative relationship between chronic low-grade inflammation and insulin resistance are not completely understood, compelling evidence suggests a pivotal role of the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Here we tested the hypothesis that either a selective pharmacological inhibition or a genetic downregulation of the NLRP3 inflammasome results in reduction of the diet-induced metabolic alterations. Male C57/BL6 wild-type mice and NLRP3 -/-littermates were fed control diet or high-fat, high-fructose diet (HD). A subgroup of HD-fed wild-type mice was treated with the NLRP3 inflammasome inhibitor BAY 11-7082 (3 mg/kg intraperitoneally [IP]). HD feeding increased plasma and hepatic lipids and impaired glucose homeostasis and renal function. Renal and hepatic injury was associated with robust increases in profibrogenic markers, while only minimal fibrosis was recorded. None of these metabolic abnormalities were detected in HD-fed NLRP3 -/-mice, and they were dramatically reduced in HD-mice treated with the NLRP3 inflammasome inhibitor. BAY 11-7082 also attenuated the diet-induced increase in NLRP3 inflammasome expression, resulting in inhibition of caspase-1 activation and interleukin (IL)-1β and IL-18 production (in liver and kidney). Interestingly, BAY 11-7082, but not gene silencing, inhibited nuclear factor (NF)-κB nuclear translocation. Overall, these results demonstrate that the selective pharmacological modulation of the NLRP3 inflammasome attenuates the metabolic abnormalities and the related organ injury/dysfunction caused by chronic exposure to HD, with effects similar to those obtained by NLRP3 gene silencing.

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BAY 11-7082 Is a Broad-Spectrum Inhibitor with Anti-Inflammatory Activity against Multiple Targets

Cited by 132 publications

References 41 publications

The Compromise of Macrophage Functions by Hyperoxia Is Attenuated by Ethacrynic Acid via Inhibition of NF-κB–Mediated Release of High-Mobility Group Box-1

The Compromise of Macrophage Functions by Hyperoxia Is Attenuated by Ethacrynic Acid via Inhibition of NF-κB–Mediated Release of High-Mobility Group Box-1

Signal Inhibitory Receptor on Leukocytes-1 Limits the Formation of Neutrophil Extracellular Traps, but Preserves Intracellular Bacterial Killing

Targeting the NLRP3 inflammasome to Reduce Diet-induced Metabolic Abnormalities in Mice

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