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Abstract Number: 1197

Febuxostat Inhibits Monosodium Urate Crystal-Induced IL-1beta Secretion and Cell Death Via ROS- and Intracellular ATP-Dependent Pathways

Johji Nomura1, Nathalie Busso2, Mizuho Tamura1, Tsunefumi Kobayashi1 and Alexander So3, 1Pharmaceutical Development Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Tokyo, Japan, 2Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland, 3Rheumatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Macrophage, ROS and inflammasome activation

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Session Information

Title: Innate Immunity and Rheumatic Disease: Signaling Mechanisms

Session Type: Abstract Submissions (ACR)

Background/Purpose: In gout, monosodium urate (MSU) crystals trigger acute inflammation. MSU has been reported to activate NLRP3 inflammasome via ROS-dependent pathways, which result in IL-1beta secretion and cell death. To date, we have shown that febuxostat, a potent inhibitor of xanthine oxidoreductase (XOR), inhibits crystal-induced IL-1beta secretion and cell death in activated macrophages. In this study, we examined its inhibitory mechanisms. Methods: Bone marrow-derived macrophages were primed, incubated with febuxostat and stimulated with MSU. IL-1beta in the supernatant, intracellular ATP, mitochondrial ROS and membrane potential were analyzed. Results: MSU treatment resulted in the production of mitochondrial ROS as well as IL-1beta secretion, and led to decreased intracellular ATP (iATP) levels and depolarization of mitochondrial membrane potential. All these intracellular mechanisms were inhibited by febuxostat. Accordingly, Mito-TEMPO, a mitochondria-targeted antioxidant, inhibited IL-1beta secretion by decreasing mitochondrial ROS production; in addition, artificially decreased iATP induced IL-1beta secretion and depolarization of membrane potential in activated macrophages. Conclusion: These results suggested that MSU induces IL-1beta and cell death via two pathways: 1) mitochondrial ROS formation, 2) iATP reduction and mitochondrial dysfunction. Both pathways can be inhibited by febuxostat, suggesting that XOR inhibition not only decreases uric acid level in the blood but also suppresses crystal-induced inflammation.


Disclosure:

J. Nomura,

Teijin Pharma Limited,

3;

N. Busso,
None;

M. Tamura,

Teijin Phama Limited,

3;

T. Kobayashi,

Teijin Pharma Limited,

3;

A. So,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/febuxostat-inhibits-monosodium-urate-crystal-induced-il-1beta-secretion-and-cell-death-via-ros-and-intracellular-atp-dependent-pathways/

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