RRC ID 67169
Author Komatsu W, Kishi H, Yagasaki K, Ohhira S.
Title Urolithin A attenuates pro-inflammatory mediator production by suppressing PI3-K/Akt/NF-κB and JNK/AP-1 signaling pathways in lipopolysaccharide-stimulated RAW264 macrophages: Possible involvement of NADPH oxidase-derived reactive oxygen species.
Journal Eur J Pharmacol
Abstract Urolithin A, a gut microbial metabolite of ellagic acid, is reported to exert anti-inflammatory effects in vitro and in vivo. However, complete mechanisms underlying the regulation of inflammatory responses by urolithin A remain unclear. This study aimed to evaluate the anti-inflammatory potential of urolithin A and its underlying mechanisms in lipopolysaccharide (LPS)-stimulated RAW264 macrophages. Urolithin A significantly attenuated the pro-inflammatory mediator production in LPS-stimulated RAW264 and mouse peritoneal macrophages. This compound significantly suppressed the LPS-elicited nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activation. The phosphorylation of Akt and c-Jun N-terminal kinase (JNK) was also inhibited by the treatment with urolithin A. Through experiments using kinase inhibitors, urolithin A abolished the LPS-induced phosphatidylinositol 3-kinase (PI3-K)/Akt/NF-κB and JNK/AP-1 signaling pathways, resulting in suppression of pro-inflammatory mediator production. Furthermore, treatment with this compound significantly reduced the intracellular accumulation of reactive oxygen species, which are known to act as secondary messengers in the activation of redox-sensitive transcription factors NF-κB and AP-1. Urolithin A treatment also diminished the LPS-evoked activation of NADPH oxidase (NOX), which is the main source of reactive oxygen species in activated macrophages. The inhibition of this activity by urolithin A led to the prevention of LPS-elicited NF-κB and AP-1 activation as well as Akt and JNK phosphorylation, resulting in the reduction of pro-inflammatory mediator production. Collectively, these results indicate that urolithin A treatment attenuates pro-inflammatory mediator production by suppressing NOX-derived reactive oxygen species-mediated PI3-K/Akt/NF-κB and JNK/AP-1 signaling pathways in LPS-stimulated macrophages.
Volume 833
Pages 411-424
Published 2018-8-15
DOI 10.1016/j.ejphar.2018.06.023
PII S0014-2999(18)30355-8
PMID 29932926
MeSH Animals Anti-Inflammatory Agents / pharmacology* Anti-Inflammatory Agents / therapeutic use Coumarins / pharmacology* Coumarins / therapeutic use Inflammation / drug therapy* Inflammation / immunology Inflammation Mediators / metabolism JNK Mitogen-Activated Protein Kinases / metabolism Lipopolysaccharides / immunology Male Mice Mice, Inbred ICR Models, Animal NADPH Oxidases / antagonists & inhibitors* NADPH Oxidases / metabolism NF-kappa B / metabolism Peritoneum / cytology Phosphatidylinositol 3-Kinase / metabolism Phosphorylation / drug effects Primary Cell Culture Proto-Oncogene Proteins c-akt / metabolism RAW 264.7 Cells Reactive Oxygen Species / immunology Reactive Oxygen Species / metabolism Signal Transduction / drug effects* Signal Transduction / immunology Transcription Factor AP-1 / metabolism p38 Mitogen-Activated Protein Kinases / metabolism
IF 3.263
Human and Animal Cells RAW 264(RCB0535)