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VU0155069 Inhibits Inflammasome Activation Independent of Phospholipase D1 Activity

VU0155069 Inhibits Inflammasome Activation Independent of Phospholipase D1 Activity

Sung Kyun Lee, Ye Seon Kim, Geon Ho Bae, Ha Young Lee, Yoe-Sik Bae

Sci Rep. 2019 Oct 4;9(1):14349.

PMID: 31586128

Abstract:

The inflammasome is a specialized multiprotein oligomer that regulates IL-1β production. Although regulation of the inflammasome is related to crucial inflammatory disorders such as sepsis, pharmacological inhibitors that effectively inhibit inflammasome activity are limited. Here, we evaluated the effects of a phospholipase D1 (PLD1)-selective inhibitor (VU0155069) against sepsis and inflammasome activation. VU0155069 strongly enhances survival rate in cecal ligation and puncture (CLP)-induced sepsis by inhibiting lung inflammation, leukocyte apoptosis, and the production of proinflammatory cytokines, especially IL-1β. VU0155069 also significantly blocked IL-1β production, caspase-1 activation, and pyroptosis caused by several inflammasome-activating signals in the bone marrow-derived macrophages (BMDMs). However, VU0155069 did not affect LPS-induced activation of signaling molecules such as MAPK, Akt, NF-κB, and NLRP3 expression in the BMDMs. VU0155069 also failed to affect mitochondrial ROS generation and calcium increase caused by nigericin or ATP, and subsequent ASC oligomerization caused by several inflammasome-activating signals. VU0155069 indirectly inhibited caspase-1 activity caused by LPS + nigericin in BMDMs independent of PLD1 activity. We demonstrated that a PLD1 inhibitor, VU0155069, shows anti-septic activity as well as inflammasome-inhibiting effects. Our results suggest that VU0155069 can be considered a novel inflammasome inhibitor.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1130067069	VU0155069		1130067-06-9	Price

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