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.
机构:
Univ Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Ali, Syed Raza
Timmer, Anjuli M.
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Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA
Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Timmer, Anjuli M.
Bilgrami, Sameera
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Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Bilgrami, Sameera
Park, Eek Joong
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Univ Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Park, Eek Joong
Eckmann, Lars
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Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Eckmann, Lars
Nizet, Victor
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Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA
Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Nizet, Victor
Karin, Michael
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Univ Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
机构:
Univ Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Ali, Syed Raza
Timmer, Anjuli M.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA
Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Timmer, Anjuli M.
Bilgrami, Sameera
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h-index: 0
机构:
Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Bilgrami, Sameera
Park, Eek Joong
论文数: 0引用数: 0
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机构:
Univ Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Park, Eek Joong
Eckmann, Lars
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h-index: 0
机构:
Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Eckmann, Lars
Nizet, Victor
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA
Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Nizet, Victor
Karin, Michael
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA
Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, Lab Signal Transduct, La Jolla, CA 92093 USA