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J Leukoc Biol. 2014 Dec;96(6):1087-100. doi: 10.1189/jlb.3A0114-005RR. Epub 2014 Sep 10.

Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation.

Author information

1
Toyama Prefectural Institute for Pharmaceutical Research, Toyama, Japan; Departments of Immunobiology and Pharmacological Genetics.
2
Departments of Immunobiology and Pharmacological Genetics, Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology, Saitama, Japan; takatsuk@med.u-toyama.ac.jp ynagai@med.u-toyama.ac.jp.
3
Toyama Prefectural Institute for Pharmaceutical Research, Toyama, Japan;
4
Departments of Immunobiology and Pharmacological Genetics, Teika Pharmaceutical, Toyama, Japan; and.
5
Departments of Immunobiology and Pharmacological Genetics.
6
Diagnostic Pathology, and.
7
Department of Natural Products Chemistry, School of Pharmacy, Iwate Medical University, Japan.
8
Immunology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Japan;
9
Toyama Prefectural Institute for Pharmaceutical Research, Toyama, Japan; Departments of Immunobiology and Pharmacological Genetics, takatsuk@med.u-toyama.ac.jp ynagai@med.u-toyama.ac.jp.

Abstract

Inflammasome activation initiates the development of many inflammatory diseases, including obesity and type 2 diabetes. Therefore, agents that target discrete activation steps could represent very important drugs. We reported previously that ILG, a chalcone from Glycyrrhiza uralensis, inhibits LPS-induced NF-κB activation. Here, we show that ILG potently inhibits the activation of NLRP3 inflammasome, and the effect is independent of its inhibitory potency on TLR4. The inhibitory effect of ILG was stronger than that of parthenolide, a known inhibitor of the NLRP3 inflammasome. GL, a triterpenoid from G. uralensis, had similar inhibitory effects on NLRP3 activity, but high concentrations of GL were required. In contrast, activation of the AIM2 inflammasome was inhibited by GL but not by ILG. Moreover, GL inhibited NLRP3- and AIM2-activated ASC oligomerization, whereas ILG inhibited NLRP3-activated ASC oligomerization. Low concentrations of ILG were highly effective in IAPP-induced IL-1β production compared with the sulfonylurea drug glyburide. In vivo analyses revealed that ILG potently attenuated HFD-induced obesity, hypercholesterolemia, and insulin resistance. Furthermore, ILG treatment improved HFD-induced macrovesicular steatosis in the liver. Finally, ILG markedly inhibited diet-induced adipose tissue inflammation and IL-1β and caspase-1 production in white adipose tissue in ex vivo culture. These results suggest that ILG is a potential drug target for treatment of NLRP3 inflammasome-associated inflammatory diseases.

KEYWORDS:

AIM2; IL-1β; caspase-1; diabetes; glycyrrhizin; obesity

PMID:
25210146
DOI:
10.1189/jlb.3A0114-005RR
[Indexed for MEDLINE]

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