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J. Biol. Chem., Vol. 279, Issue 24, 25024-25038, June 11, 2004

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Arachidonic Acid Release from Mammalian Cells Transfected with Human Groups IIA and X Secreted Phospholipase A₂ Occurs Predominantly during the Secretory Process and with the Involvement of Cytosolic Phospholipase A₂-^*

Carine M. Mounier, Farideh Ghomashchi, Margaret R. Lindsay, Scott James, Alan G. Singer, Robert G. Parton, and Michael H. Gelb¶

From the Departments of Chemistry and Biochemistry, University of Washington, Seattle, Washington 98195 and the Institute for Molecular Biosciences and Centre for Microscopy and Microanalysis and School of Biomedical Sciences, University of Queensland, Brisbane, 4072 Queensland, Australia

Stable expression of human groups IIA and X secreted phospholipases A₂ (hGIIA and hGX) in CHO-K1 and HEK293 cells leads to serum- and interleukin-1-promoted arachidonate release. Using mutant CHO-K1 cell lines, it is shown that this arachidonate release does not require heparan sulfate proteoglycan- or glycosylphosphatidylinositol-anchored proteins. It is shown that the potent secreted phospholipase A₂ inhibitor Me-Indoxam is cell-impermeable. By use of Me-Indoxam and the cell-impermeable, secreted phospholipase A₂ trapping agent heparin, it is shown that hGIIA liberates free arachidonate prior to secretion from the cell. With hGX-transfected CHO-K1 cells, arachidonate release occurs before and after enzyme secretion, whereas all of the arachidonate release from HEK293 cells occurs prior to enzyme secretion. Immunocytochemical studies by confocal laser and electron microscopies show localization of hGIIA to the cell surface and Golgi compartment. Additional results show that the interleukin-1-dependent release of arachidonate is promoted by secreted phospholipase A₂ expression and is completely dependent on cytosolic (group IVA) phospholipase A₂. These results along with additional data resolve the paradox that efficient arachidonic acid release occurs with hGIIA-transfected cells, and yet exogenously added hGIIA is poorly able to liberate arachidonic acid from mammalian cells.

Received for publication, December 1, 2003 , and in revised form, March 5, 2004.

Note Added in Proof—Recently, Arm and co-workers have shown that disruption of the mouse group V sPLA₂ gene leads to an 50% reduction in the amount of arachidonic acid liberated from zymosan-stimulated peritoneal macrophages (58), and yet earlier studies showed that the disruption of the cPLA₂- gene leads to complete loss of arachidonic acid from these cells (59). Thus, it appears that group V sPLA₂ action somehow augments the function of cPLA₂- in peritoneal macrophages. We have found that pyrrophenone blocks all of the arachidonate release from zymosan-stimulated mouse peritoneal macrophages, but 1 and 10 µM Me-Indoxam is without effect (data not shown). These results are consistent with the gene disruption studies (58, 59) and further suggest that mouse group V is able to augment the action of cPLA₂- and that the sPLA₂ acts prior to release from the cells. Thus our conclusions in the present study derived from transfected cells appear to be relevant to at least some non-transfectant cells/agonist systems.

^* This work was supported by National Institutes of Health Grants HL36835 and HL50040 (to M. H. G.) and a program grant from the National Health and Medical Research Council of Australia (to R. G. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental figures and text.

^¶ To whom correspondence should be addressed: Depts. of Chemistry and Biochemistry, Campus Box 351700, University of Washington, Seattle, WA 98195. Fax: 206-685-8665; E-mail: gelb{at}chem.washington.edu.

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