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A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation

A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation
Lee, JW[Lee, Ji-Won]Kim, LE[Kim, Leah Eunjung]Shim, HJ[Shim, Hyun-Jung]Kim, EK[Kim, Eun-Kyoung]Hwang, WC[Hwang, Won Chan]Min, DS[Min, Do Sik]Yu, SW[Yu, Seong-Woon]
DGIST Authors
Lee, JW[Lee, Ji-Won]; Shim, HJ[Shim, Hyun-Jung]; Kim, EK[Kim, Eun-Kyoung]Yu, SW[Yu, Seong-Woon]
Issue Date
Biochemical and Biophysical Research Communications, 474(3), 587-593
Article Type
Adaptor ProteinAdenosine TriphosphateAnti-Inflammatory AgentCarrier ProteinCells by Body AnatomyCryopyrinDrug MechanismEnzyme ActivationHumanHuman CellInflammasomeInnate ImmunityInterleukin-1 BetaInterleukin-1 Beta Converting EnzymeLigandMacrophageMitochondriaMitochondrial Membrane PotentialMitochondrionMonocyteN Sec Butyl 1 (2 Chlorophenyl) N Methyl 3 IsoquinolinecarboxamideNLRP3Nucleotide Binding Oligomerization Domain Like ReceptorOligomerizationPriority JournalProtein AssemblyRo5-4864Signal TransductionSuperoxideTSPOUnclassified Drug
Ro5-4864 and PK11195, prototypical synthetic ligands of translocator protein 18 kDa (TSPO), have shown anti-inflammatory effects in several models of inflammatory diseases; however, their biochemical mechanisms remain poorly understood. Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation as a part of the innate immune system, has been implicated in a variety of inflammatory diseases. Here, we demonstrate for the first time that TSPO ligands, especially Ro5-4864, potently suppressed ATP-induced NLRP3 inflammasome activation in THP-1 and BMDM cells. Detailed action mechanism was further investigated in THP-1 cells. Ro5-4864 efficiently attenuated NLRP3 translocation to mitochondria, inflammasome assembly/oligomerization, activation of caspase-1, and subsequent secretion of the mature forms of interleukin-1β and -18. Ro5-4864 also reduced the production of mitochondrial superoxide and preserved the mitochondrial membrane potential in ATP-treated cells, suggesting that Ro5-4864 may act on mitochondria or more upstream targets in NLRP3 inflammasome signaling. We also observed the distinct effects of the TSPO ligands between THP-1 monocytes and macrophages, which suggested different NLRP3 inflammasome signaling depending on cell type. Collectively, our novel findings demonstrate that Ro5-4864 effectively inhibited ATP-induced NLRP3 inflammasome activation through the prevention of mitochondrial perturbation. Our results indicate Ro5-4864 as a promising candidate for the treatment of NLRP3 inflammasome-related diseases. © 2016 Elsevier Inc. All rights reserved.
Elsevier B.V.
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Brain and Cognitive SciencesLab of Neuro-Metabolism & Neurometabolomic Research Center1. Journal Articles

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