Calcium-Independent Phospholipase A2β Is Dispensable in Inflammasome Activation and Its Inhibition by Bromoenol Lactone (original) (raw)
Article navigation
Review Articles| July 01 2009
aDepartment of Pathology and Comprehensive Cancer Center, and
Search for other works by this author on:
aDepartment of Pathology and Comprehensive Cancer Center, and
Search for other works by this author on:
aDepartment of Pathology and Comprehensive Cancer Center, and
Search for other works by this author on:
bDepartment of Internal Medicine, University of Michigan Medical School, Ann Arbor, Mich.,
Search for other works by this author on:
cDepartment of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, and
Search for other works by this author on:
dDepartment of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Mo., USA
Search for other works by this author on:
bDepartment of Internal Medicine, University of Michigan Medical School, Ann Arbor, Mich.,
Search for other works by this author on:
dDepartment of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Mo., USA
Search for other works by this author on:
cDepartment of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, and
Search for other works by this author on:
aDepartment of Pathology and Comprehensive Cancer Center, and
Search for other works by this author on:
J Innate Immun (2009) 1 (6): 607–617.
Abstract
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.
This content is only available via PDF.
© 2009 S. Karger AG, Basel
2009
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.