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

Journal of Leukocyte Biology

Ying-Cing Lin²  Ai-Jen Yang²  Kuo-Chin Huang, and³  Yi-Chieh Lin²  Shih-Ting Tsao²  Yi-Hsiang Liao⁴  Chen-Tsung Huang²  Wan Wan Lin,,¹ 

[1] Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; The Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, TaiwanDepartment of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan;Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan;Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan;  Department of Pharmacy, Far Eastern Memorial Hospital, New Taipei City, Taiwan;

关键词: statins;    IL-1β;    mevalonate kinase deficiency;    isoprenoids;    inflammasome;   

DOI  :  10.1189/jlb.0812409

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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 LysoTracker 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.

【 授权许可】

Unknown