Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 93, Issue 2, Pages 289-299Publisher
OXFORD UNIV PRESS
DOI: 10.1189/jlb.0812409
Keywords
statins; IL-1 beta; mevalonate kinase deficiency; isoprenoids; inflammasome
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Funding
- National Science Council [NSC 97-2314-B-002-017-MY3, NSC 100-2314-B-002-075]
- National Health Research Institute, Taiwan [NHRI-EX100-10052SI]
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Recent studies have demonstrated the stimulatory effects of HMG-CoA reductase inhibitors, statins, on IL-1 beta secretion in monocytes and suggest a crucial role for iso-prenoids in the inhibition of caspase-1 activity. In this study, we further elucidated the molecular mechanisms underlying the stimulatory effects of statins on caspase-1. Three commonly recognized mechanistic models for NLRP3 inflammasome activation (i.e., ATP/P2X7/K+ efflux, ROS production, and lysosomal rupture) were investigated in statin-stimulated human THP-1 monocytes. We found that fluvastatin and lovastatin can synergize with LPS to trigger inflammasome activation. Moreover, statin-induced caspase-1 activation and IL-1 beta production in LPS-primed THP-1 cells are dependent on GGPP deficiency and P2X7 activation. In particular, increased ATP release accounts for the action of statins in P2X7 activation. We also provide evidence that statin-induced moderate ROS elevation is involved in this event. Moreover, the cathepsin B inhibitor was shown to reduce statin-induced IL-1 beta secretion. Consistently statins can induce cathepsin B activation and lysosomal rupture, as evidenced by Lyso-Tracker staining. Statins also increase intracellular ATP secretion and IL-1 beta release in primary human monocytes and murine macrophages. Notably, exogenous ATP-elicited P2X7 activation and consequent IL-1 beta release, an index of direct NLRP3 inflammasome activation, were not altered by statins. Taken together, statin-induced enhancement of inflammasome activation in monocytes and macrophages covers multiple mechanisms, including increases in ATP re-lease, ROS production, and lysosomal rupture. These data not only shed new insight into isoprenylation-dependent regulation of caspase-1 but also unmask mechanisms for statin-elicited inflammasome activation. J. Leukoc. Biol. 93: 289-299; 2013.
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