HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Adam-Klages, S. Articles by Krönke, M. Search for Related Content PubMed PubMed Citation Articles by Adam-Klages, S. Articles by Krönke, M. Pubmed/NCBI databases Substance via MeSH

Caspase-Mediated Inhibition of Human Cytosolic Phospholipase A₂ During Apoptosis¹

Institut für Immunologie, Christian-Albrechts-Universität Kiel, Kiel, Germany

Activation of cytosolic phospholipase A₂ (cPLA₂) is an essential step in the initiation of the cascade of enzymatic reactions leading to the generation of proinflammatory lipid mediators. Hence, the regulation of cPLA₂ is a key event in the induction of inflammatory responses. cPLA₂ is activated, in part, by apoptotic stimuli such as TNF or Fas ligand. Apoptosis, however, does not provoke an inflammatory response. Here, we demonstrate that cPLA₂ is cleaved by caspase-3 and/or a related caspase in HeLa cells undergoing apoptosis. Mutation of a predicted caspase-3 cleavage site abolishes cPLA₂ processing both in vitro and in intact cells. The 70-kDa cleavage product of cPLA₂ itself has no catalytic function, while inhibition of cleavage results in an increased enzymatic activity. Additionally, overexpression of the 70-kDa fragment appears to produce a dominant negative effect on endogenous cPLA₂ activity. In HeLa cells, cPLA₂ activity was dispensable for the course of apoptosis. We cannot rule out, however, that cPLA₂ activity is involved in the induction of apoptosis in other cell types. Taken together, our results suggest that the enzymatic activity of cPLA₂ is specifically inhibited by caspase-mediated cleavage during apoptosis. The inactivation of cPLA₂ represents a previously unrecognized mechanism for avoiding an inflammatory reaction against apoptotic cells.

This article has been cited by other articles:

				S. Tashiro, T. Sumi, N. Uozumi, T. Shimizu, and T. Nakamura B-Myb-Dependent Regulation of c-Myc Expression by Cytosolic Phospholipase A2 J. Biol. Chem., April 23, 2004; 279(17): 17715 - 17722. [Abstract] [Full Text] [PDF]

				L. Foghsgaard, U. Lademann, D. Wissing, B. Poulsen, and M. Jaattela Cathepsin B Mediates Tumor Necrosis Factor-induced Arachidonic Acid Release in Tumor Cells J. Biol. Chem., October 11, 2002; 277(42): 39499 - 39506. [Abstract] [Full Text] [PDF]

				S. Grewal, E. E. Morrison, S. Ponnambalam, and J. H. Walker Nuclear localisation of cytosolic phospholipase A2-{alpha} in the EA.hy.926 human endothelial cell line is proliferation dependent and modulated by phosphorylation J. Cell Sci., January 12, 2002; 115(23): 4533 - 4543. [Abstract] [Full Text] [PDF]

				A. N. Fonteh, C. R. Marion, B. J. Barham, M. B. Edens, G.-i. Atsumi, J. M. Samet, K. P. High, and F. H. Chilton Enhancement of Mast Cell Survival: A Novel Function of Some Secretory Phospholipase A2 Isotypes J. Immunol., October 15, 2001; 167(8): 4161 - 4171. [Abstract] [Full Text] [PDF]

				S. R. Panini, L. Yang, A. E. Rusinol, M. S. Sinensky, J. V. Bonventre, and C. C. Leslie Arachidonate metabolism and the signaling pathway of induction of apoptosis by oxidized LDL/oxysterol J. Lipid Res., October 1, 2001; 42(10): 1678 - 1686. [Abstract] [Full Text] [PDF]

				N.-E. El Mahdani, M. Ameyar, Z. Cai, O. Colard, J. Masliah, and S. Chouaib Resistance to TNF-Induced Cytotoxicity Correlates with an Abnormal Cleavage of Cytosolic Phospholipase A2 J. Immunol., December 15, 2000; 165(12): 6756 - 6761. [Abstract] [Full Text] [PDF]

				I. Walev, J. Klein, M. Husmann, A. Valeva, S. Strauch, H. Wirtz, O. Weichel, and S. Bhakdi Potassium Regulates IL-1{beta} Processing Via Calcium-Independent Phospholipase A2 J. Immunol., May 15, 2000; 164(10): 5120 - 5124. [Abstract] [Full Text] [PDF]

				G.-i. Atsumi, M. Murakami, K. Kojima, A. Hadano, M. Tajima, and I. Kudo Distinct Roles of Two Intracellular Phospholipase A2s in Fatty Acid Release in the Cell Death Pathway. PROTEOLYTIC FRAGMENT OF TYPE IVA CYTOSOLIC PHOSPHOLIPASE A2alpha INHIBITS STIMULUS-INDUCED ARACHIDONATE RELEASE, WHEREAS THAT OF TYPE VI Ca2+-INDEPENDENT PHOSPHOLIPASE A2 AUGMENTS SPONTANEOUS FATTY ACID RELEASE J. Biol. Chem., June 9, 2000; 275(24): 18248 - 18258. [Abstract] [Full Text] [PDF]

				A. N. Fonteh, T. LaPorte, D. Swan, and M. A. McAlexander A Decrease in Remodeling Accounts for the Accumulation of Arachidonic Acid in Murine Mast Cells Undergoing Apoptosis J. Biol. Chem., January 5, 2001; 276(2): 1439 - 1449. [Abstract] [Full Text] [PDF]