Calcium-independent phospholipase A2 (iPLA2) has been suggested to play an important role in the activation of caspase-1 induced by lipopolysaccharides (LPS). Here, we used pharmacological and genetic approaches to study the role of iPLA2 in the activation of caspase-1. Bromoenol lactone (BEL), an inhibitor that was originally used to support a role for iPLA2 in the secretion of IL-1β, prevented caspase-1 activation induced by LPS and ATP as described, and also activation triggered by Salmonella infection and cytosolic flagellin, which rely on the Nlrc4 inflammasome. Analysis of BEL enantiomers showed that the S-BEL form was more effective than R-BEL in inhibiting the inflammasome, suggesting a role for iPLA2β. However, caspase-1 activation and IL-1β secretion and their inhibition by BEL were unimpaired in macrophages deficient in iPLA2β. BEL was originally identified as an inhibitor of serine proteases. Consistent with the latter, the serine proteases inhibitors TPCK, TLCK and AAF-cmk prevented the activation of the Nlrc4 and Nlrp3 inflammasomes while pan-cathepsin inhibitors were ineffective. These results indicate that iPLA2β is not critical for caspase-1 activation as currently proposed. Instead, the results suggest that serine protease(s) targeted by BEL may play a critical role in the activation of the inflammasome triggered by microbial stimuli.
© 2009 S. Karger AG, Basel
- Phospholipase A2
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Dr. Gabriel Núñez
Department of Pathology and Comprehensive Cancer Center
University of Michigan Medical School
1500 E. Medical Center Drive, Ann Arbor, MI 48109 (USA)
Tel. +1 734 764 8514, Fax +1 734 647 9654, E-Mail email@example.com
Received: March 24, 2009
Accepted after revision: April 30, 2009
Published online: July 1, 2009
Number of Print Pages : 11
Number of Figures : 7, Number of Tables : 0, Number of References : 40
Journal of Innate Immunity
Vol. 1, No. 6, Year 2009 (Cover Date: October 2009)
Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)
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