HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation

Yi Hsiang Liao, Yi Chieh Lin, Shih Ting Tsao, Ying Cing Lin, Ai Jen Yang, Chen Tsung Huang, Kuo Chin Huang, Wan Wan Lin

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30 Citations (Scopus)

Abstract

Recent studies have demonstrated the stimulatory effects of HMG-CoA reductase inhibitors, statins, on IL-1β secretion in monocytes and suggest a crucial role for isoprenoids 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-1β 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-1β 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-1β release in primary human monocytes and murine macrophages. Notably, exogenous ATP-elicited P2X7 activation and consequent IL-1β 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 release, 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.
Original languageEnglish
Pages (from-to)289-299
Number of pages11
JournalJournal of Leukocyte Biology
Volume93
Issue number2
DOIs
Publication statusPublished - Feb 8 2013

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Caspase 1
Monocytes
Adenosine Triphosphate
Inflammasomes
Interleukin-1
Rupture
Cathepsin B
fluvastatin
Macrophages
Prenylation
Lovastatin
Terpenes

Keywords

  • Il-1

Cite this

Liao, Y. H., Lin, Y. C., Tsao, S. T., Lin, Y. C., Yang, A. J., Huang, C. T., ... Lin, W. W. (2013). HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation. Journal of Leukocyte Biology, 93(2), 289-299. https://doi.org/10.1189/jlb.0812409

HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation. / Liao, Yi Hsiang; Lin, Yi Chieh; Tsao, Shih Ting; Lin, Ying Cing; Yang, Ai Jen; Huang, Chen Tsung; Huang, Kuo Chin; Lin, Wan Wan.

In: Journal of Leukocyte Biology, Vol. 93, No. 2, 08.02.2013, p. 289-299.

Research output: Contribution to journalArticle

Liao, YH, Lin, YC, Tsao, ST, Lin, YC, Yang, AJ, Huang, CT, Huang, KC & Lin, WW 2013, 'HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation', Journal of Leukocyte Biology, vol. 93, no. 2, pp. 289-299. https://doi.org/10.1189/jlb.0812409
Liao, Yi Hsiang ; Lin, Yi Chieh ; Tsao, Shih Ting ; Lin, Ying Cing ; Yang, Ai Jen ; Huang, Chen Tsung ; Huang, Kuo Chin ; Lin, Wan Wan. / HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation. In: Journal of Leukocyte Biology. 2013 ; Vol. 93, No. 2. pp. 289-299.
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