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• W2140182017 abstract "We have recently reported that members of the heparin-binding group II subfamily of secretory PLA2s (sPLA2s) (types IIA and V), when transfected into 293 cells, released [3H]arachidonic acid (AA) preferentially in response to interleukin-1 (IL-1) and acted as “signaling” PLA2s that were functionally coupled with prostaglandin biosynthesis. Here we show that these group II subfamily sPLA2s and the type X sPLA2 behave in a different manner, the former being more efficiently coupled with the prostaglandin-biosynthetic pathway than the latter, in 293 transfectants. Type X sPLA2, which bound only minimally to cell surface proteoglycans, augmented the release of both [3H]AA and [3H]oleic acid in the presence of serum but not IL-1. Both types IIA and V sPLA2, the AA released by which was efficiently converted to prostaglandin E2, markedly augmented IL-1-induced expression of cyclooxygenase (COX)-2 in a heparin-sensitive fashion, whereas type X sPLA2 lacked the ability to augment COX-2 expression, thereby exhibiting the poor prostaglandin E2-biosynthetic response unless either of the COX isozymes was forcibly introduced into type X sPLA2-expressing cells. Implication of phospholipid scramblase, an enzyme responsible for the perturbation of plasma membrane asymmetry, revealed that the scramblase-transfected cells became more sensitive to types IIA and V, but not X, sPLA2, releasing both [3H]AA and [3H]oleic acid in an IL-1-independent manner. Thus, although phospholipid scramblase-mediated alteration in plasma membrane asymmetry actually led to the increased cellular susceptibility to the group II subfamily of sPLA2s, several lines of evidence suggest that it does not entirely mimic their actions on cells after IL-1 signaling. Interestingly, coexpression of type IIA or V, but not X, sPLA2 and phospholipid scramblase resulted in a marked reduction in cell growth, revealing an unexplored antiproliferative aspect of particular classes of sPLA2. We have recently reported that members of the heparin-binding group II subfamily of secretory PLA2s (sPLA2s) (types IIA and V), when transfected into 293 cells, released [3H]arachidonic acid (AA) preferentially in response to interleukin-1 (IL-1) and acted as “signaling” PLA2s that were functionally coupled with prostaglandin biosynthesis. Here we show that these group II subfamily sPLA2s and the type X sPLA2 behave in a different manner, the former being more efficiently coupled with the prostaglandin-biosynthetic pathway than the latter, in 293 transfectants. Type X sPLA2, which bound only minimally to cell surface proteoglycans, augmented the release of both [3H]AA and [3H]oleic acid in the presence of serum but not IL-1. Both types IIA and V sPLA2, the AA released by which was efficiently converted to prostaglandin E2, markedly augmented IL-1-induced expression of cyclooxygenase (COX)-2 in a heparin-sensitive fashion, whereas type X sPLA2 lacked the ability to augment COX-2 expression, thereby exhibiting the poor prostaglandin E2-biosynthetic response unless either of the COX isozymes was forcibly introduced into type X sPLA2-expressing cells. Implication of phospholipid scramblase, an enzyme responsible for the perturbation of plasma membrane asymmetry, revealed that the scramblase-transfected cells became more sensitive to types IIA and V, but not X, sPLA2, releasing both [3H]AA and [3H]oleic acid in an IL-1-independent manner. Thus, although phospholipid scramblase-mediated alteration in plasma membrane asymmetry actually led to the increased cellular susceptibility to the group II subfamily of sPLA2s, several lines of evidence suggest that it does not entirely mimic their actions on cells after IL-1 signaling. Interestingly, coexpression of type IIA or V, but not X, sPLA2 and phospholipid scramblase resulted in a marked reduction in cell growth, revealing an unexplored antiproliferative aspect of particular classes of sPLA2. phospholipase A2 secretory PLA2 cytosolic PLA2 Ca2+-independent PLA2 arachidonic acid oleic acid prostaglandin prostaglandin E2 cyclooxygenase interleukin-1 fetal calf serum bromoenol lactone phosphatidylethanolamine phosphatidylcholine polymerase chain reaction Phospholipase A2(PLA2)1 enzymes catalyze the hydrolysis of membrane glycerophospholipids at thesn-2 position, liberating free fatty acids and lysophospholipids, and play crucial roles in regulating arachidonic acid (AA) metabolism and phospholipid remodeling. Recent advances in molecular and cellular biology have led to the identification of more than 10 mammalian PLA2 isozymes, which are subdivided into several groups based upon their structures, enzymatic characteristics, subcellular distributions, and cellular functions (1Murakami M. Nakatani Y. Atsumi G. Inoue K. Kudo I. Crit. Rev. Immunol. 1997; 17: 225-283Crossref PubMed Google Scholar, 2Dennis E.A. Trends Biochem. Sci. 1997; 22: 1-2Abstract Full Text PDF PubMed Scopus (756) Google Scholar). Among the intracellular PLA2 isoforms, cytosolic Ca2+-dependent PLA2(cPLA2α; type IV) plays an essential role in the production of lipid mediators in response to various stimuli (3Leslie C.C. J. Biol. Chem. 1997; 272: 16709-16712Abstract Full Text Full Text PDF PubMed Scopus (740) Google Scholar), whereas cytosolic Ca2+-independent PLA2(iPLA2; type VI) is crucial in phospholipid remodeling (4Balsinde J. Dennis E.A. J. Biol. Chem. 1997; 272: 16069-16072Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar).Secretory PLA2s (sPLA2s) comprise the largest family of PLA2 enzymes, and six isozymes have been identified in mammals (5Tischfield J.A. J. Biol. Chem. 1997; 272: 17247-17250Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 6Ishizaki J. Suzuki N. Higashino K. Yokota Y. Ono T. Kawamoto K. Fujii N. Arita H. Hanasaki K. J. Biol. Chem. 1999; 274: 24973-24979Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). Type IB sPLA2(sPLA2-IB), also known as pancreatic PLA2, is essential for the digestion of dietary phospholipids in the gastroenteric tract and may also participate in the regulation of cellular responses in various tissues via M-type sPLA2receptor-mediated processes (7Ishizaki J. Hanasaki K. Higashino K. Kishino J. Kikuchi N. Ohara O. Arita H. J. Biol. Chem. 1994; 269: 5897-5904Abstract Full Text PDF PubMed Google Scholar). Of four closely related sPLA2s types IIA, IIC, IID, and V (the group II subfamily), the genes for which are clustered at the same chromosomal locus (5Tischfield J.A. J. Biol. Chem. 1997; 272: 17247-17250Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 6Ishizaki J. Suzuki N. Higashino K. Yokota Y. Ono T. Kawamoto K. Fujii N. Arita H. Hanasaki K. J. Biol. Chem. 1999; 274: 24973-24979Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar), sPLA2-IIA is the most widely distributed isozyme in the human and rat, and its expression is often dramatically induced by proinflammatory stimuli (8Pfeilschifter J. Schalkwijk C. Briner V.A. van den Bosch H. J. Clin. Invest. 1993; 92: 2516-2523Crossref PubMed Scopus (208) Google Scholar, 9Kuwata H. Nakatani Y. Murakami M. Kudo I. J. Biol. Chem. 1998; 273: 1733-1740Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). sPLA2-V, the isozyme closely related to sPLA2-IIA (10Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar), is widely expressed in various tissues of mouse and hearts of human and rat, is also inducible by proinflammatory stimuli, and appears to substitute for sPLA2-IIA in some cells (11Sawada H. Murakami M. Enomoto A. Shimbara S. Kudo I. Eur. J. Biochem. 1999; 263: 826-835Crossref PubMed Scopus (83) Google Scholar, 12Balboa M.A. Balsinde J. Winstead M.V. Tischfield J.A. Dennis E.A. J. Biol. Chem. 1996; 271: 32381-32384Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 13Reddy S.T. Winstead M.V. Tischfield J.A. Herschman H.R. J. Biol. Chem. 1997; 272: 13591-13596Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). Both sPLA2s-IIA and -V are capable of amplifying the stimulus-initiated immediate and delayed phases of AA metabolism by autocrine, paracrine, and juxtacrine mechanisms (8Pfeilschifter J. Schalkwijk C. Briner V.A. van den Bosch H. J. Clin. Invest. 1993; 92: 2516-2523Crossref PubMed Scopus (208) Google Scholar, 9Kuwata H. Nakatani Y. Murakami M. Kudo I. J. Biol. Chem. 1998; 273: 1733-1740Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 10Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar, 11Sawada H. Murakami M. Enomoto A. Shimbara S. Kudo I. Eur. J. Biochem. 1999; 263: 826-835Crossref PubMed Scopus (83) Google Scholar, 12Balboa M.A. Balsinde J. Winstead M.V. Tischfield J.A. Dennis E.A. J. Biol. Chem. 1996; 271: 32381-32384Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 13Reddy S.T. Winstead M.V. Tischfield J.A. Herschman H.R. J. Biol. Chem. 1997; 272: 13591-13596Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 14Reddy S.T. Herschman H.R. J. Biol. Chem. 1996; 271: 186-191Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 16Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, 17Tada K. Murakami M. Kambe T. Kudo I. J. Immunol. 1998; 161: 5008-5015PubMed Google Scholar), and their functions appear to depend on their cell surface proteoglycan-binding abilities under certain (15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 16Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, 17Tada K. Murakami M. Kambe T. Kudo I. J. Immunol. 1998; 161: 5008-5015PubMed Google Scholar, 18Murakami M. Kudo I. Inoue K. J. Biol. Chem. 1993; 268: 839-844Abstract Full Text PDF PubMed Google Scholar, 19Suga H. Murakami M. Kudo I. Inoue K. Eur. J. Biochem. 1993; 218: 807-813Crossref PubMed Scopus (70) Google Scholar, 20Murakami M. Nakatani Y. Kudo I. J. Biol. Chem. 1996; 271: 30041-30051Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 21Polgar J. Kramer R.M. Um S.L. Jakubowski J.A. Clemetson K.J. Biochem. J. 1997; 327: 259-265Crossref PubMed Scopus (16) Google Scholar), if not all (22Atsumi G. Murakami M. Tajima M. Shimbara S. Hara N. Kudo I. Biochim. Biophys. Acta. 1997; 1349: 43-54Crossref PubMed Scopus (88) Google Scholar, 23Koduri R.S. Baker S.F. Snitko Y. Han S.-K. Cho W. Wilton D.C. Gelb M.H. J. Biol. Chem. 1998; 273: 32142-32153Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar), conditions. In contrast, sPLA2-IIC, which exhibits minimal cell surface proteoglycan-binding capacity, does not augment AA metabolism significantly (15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar). AA release by the group II subfamily of sPLA2s generally occurs in activated, but not resting, cells (1Murakami M. Nakatani Y. Atsumi G. Inoue K. Kudo I. Crit. Rev. Immunol. 1997; 17: 225-283Crossref PubMed Google Scholar, 15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 24Hara S. Kudo I. Inoue K. J. Biochem. ( Tokyo ). 1991; 110: 163-165Crossref PubMed Scopus (60) Google Scholar, 25Murakami M. Kudo I. Inoue K. FEBS Lett. 1991; 294: 247-251Crossref PubMed Scopus (94) Google Scholar), leading us to formulate the hypothesis that membrane perturbation during cell activation is required for sPLA2-mediated membrane phospholipid hydrolysis. sPLA2-IID and sPLA2-X are very recently discovered sPLA2 isozymes (6Ishizaki J. Suzuki N. Higashino K. Yokota Y. Ono T. Kawamoto K. Fujii N. Arita H. Hanasaki K. J. Biol. Chem. 1999; 274: 24973-24979Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 26Cupillard L. Koumanov K. Mattei M.-G. Lazdunski M. Lambeau G. J. Biol. Chem. 1997; 272: 15745-15752Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar). sPLA2-IID belongs to the group II subfamily, is expressed more widely than sPLA2-IIA in the mouse, and is, like sPLA2-IIA (8Pfeilschifter J. Schalkwijk C. Briner V.A. van den Bosch H. J. Clin. Invest. 1993; 92: 2516-2523Crossref PubMed Scopus (208) Google Scholar, 9Kuwata H. Nakatani Y. Murakami M. Kudo I. J. Biol. Chem. 1998; 273: 1733-1740Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar) and sPLA2-V (11Sawada H. Murakami M. Enomoto A. Shimbara S. Kudo I. Eur. J. Biochem. 1999; 263: 826-835Crossref PubMed Scopus (83) Google Scholar), up-regulated following proinflammatory stimuli (6Ishizaki J. Suzuki N. Higashino K. Yokota Y. Ono T. Kawamoto K. Fujii N. Arita H. Hanasaki K. J. Biol. Chem. 1999; 274: 24973-24979Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). sPLA2-X possesses some structural features characteristic of both sPLA2-IB and sPLA2-IIA and is mainly expressed in organs associated with immune responses. Although enzymatic properties of these newly discovered sPLA2 isozymes have been partially characterized, their cellular functions remain unknown.Prostaglandin (PG) biosynthesis generally occurs in two distinct phases, the immediate and delayed responses (1Murakami M. Nakatani Y. Atsumi G. Inoue K. Kudo I. Crit. Rev. Immunol. 1997; 17: 225-283Crossref PubMed Google Scholar, 5Tischfield J.A. J. Biol. Chem. 1997; 272: 17247-17250Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 9Kuwata H. Nakatani Y. Murakami M. Kudo I. J. Biol. Chem. 1998; 273: 1733-1740Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 10Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar, 12Balboa M.A. Balsinde J. Winstead M.V. Tischfield J.A. Dennis E.A. J. Biol. Chem. 1996; 271: 32381-32384Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 13Reddy S.T. Winstead M.V. Tischfield J.A. Herschman H.R. J. Biol. Chem. 1997; 272: 13591-13596Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar,15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 16Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, 17Tada K. Murakami M. Kambe T. Kudo I. J. Immunol. 1998; 161: 5008-5015PubMed Google Scholar, 18Murakami M. Kudo I. Inoue K. J. Biol. Chem. 1993; 268: 839-844Abstract Full Text PDF PubMed Google Scholar, 19Suga H. Murakami M. Kudo I. Inoue K. Eur. J. Biochem. 1993; 218: 807-813Crossref PubMed Scopus (70) Google Scholar, 20Murakami M. Nakatani Y. Kudo I. J. Biol. Chem. 1996; 271: 30041-30051Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). Agonists that rapidly raise cytoplasmic Ca2+levels elicit the immediate response, which occurs within minutes and requires functional coupling between pre-existing PG-biosynthetic enzymes. Signaling PLA2s, including cPLA2, sPLA2-IIA, and sPLA2-V, can supply AA to the constitutive cyclooxygenase (COX) isoform COX-1 or to the preinduced COX-2, and which COX isoforms are utilized appears to depend on the types of cell and stimulus and the amounts of AA released at the moment when PG generation takes place (10Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar, 12Balboa M.A. Balsinde J. Winstead M.V. Tischfield J.A. Dennis E.A. J. Biol. Chem. 1996; 271: 32381-32384Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 13Reddy S.T. Winstead M.V. Tischfield J.A. Herschman H.R. J. Biol. Chem. 1997; 272: 13591-13596Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 16Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar). The delayed PG production is accompanied by the continuous supply of AA over long culture periods spanning several hours. Inducible COX-2 is an absolute requirement for this sustained response, in which cPLA2 and the group II subfamily of sPLA2s (IIA and V) function as an initiator and amplifier, respectively (9Kuwata H. Nakatani Y. Murakami M. Kudo I. J. Biol. Chem. 1998; 273: 1733-1740Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 10Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar, 13Reddy S.T. Winstead M.V. Tischfield J.A. Herschman H.R. J. Biol. Chem. 1997; 272: 13591-13596Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 16Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, 17Tada K. Murakami M. Kambe T. Kudo I. J. Immunol. 1998; 161: 5008-5015PubMed Google Scholar, 18Murakami M. Kudo I. Inoue K. J. Biol. Chem. 1993; 268: 839-844Abstract Full Text PDF PubMed Google Scholar, 19Suga H. Murakami M. Kudo I. Inoue K. Eur. J. Biochem. 1993; 218: 807-813Crossref PubMed Scopus (70) Google Scholar, 20Murakami M. Nakatani Y. Kudo I. J. Biol. Chem. 1996; 271: 30041-30051Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar).In the present study, we examined the functional properties of distinct sPLA2 isozymes, namely types IIA, V, and X, by overexpressing them in human embryonic kidney 293 cells. We provide evidence that sPLA2-X acts on cells in a manner different from the heparin-binding group II subfamily of sPLA2s. The heparin-binding sPLA2s-IIA and -V, but not the heparin-nonbinding sPLA2-X, have the ability to up-regulate the cytokine-induced COX-2 expression, which leads to efficient delayed PG biosynthesis. Experiments involving phospholipid scramblase, a plasma membrane protein that accelerates the transbilayer movement of phospholipids (27Zhou Q. Zhao J. Stout J.G. Luhm R.A. Wiedmer T. Sims P.J. J. Biol. Chem. 1997; 272: 18240-18244Abstract Full Text Full Text PDF PubMed Scopus (360) Google Scholar), revealed that altered membrane asymmetry indeed leads to increased cellular susceptibility to the group II subfamily of sPLA2s.DISCUSSIONWe have previously analyzed the functional coupling between various PLA2 and COX isozymes after transfection into 293 and CHO cells (15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 16Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, 20Murakami M. Nakatani Y. Kudo I. J. Biol. Chem. 1996; 271: 30041-30051Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). In the present study, we established stable transfectants expressing sPLA2-X and directly compared its AA-releasing and PG-producing capacities with other PLA2s. Several lines of evidence indicate that the regulatory effects of sPLA2-X on AA metabolism and phospholipid turnover differ from those of the group II subfamily of sPLA2s. The properties of each PLA2 trasnfectants, which have been demonstrated in our current studies (15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 16Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar), are summarized in TableI.We showed that sPLA2-X induces the release of both [3H]AA and [3H]OA in the presence of FCS but not IL-1 (Fig. 1), indicating that this sPLA2 isozyme mediates nonspecific release of fatty acids during cell culture, as does iPLA2 (15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar). This property contrasts markedly with those of the group II subfamily members sPLA2-IIA and sPLA2-V, which release [3H]AA in preference to [3H]OA in response to IL-1, as does cPLA2(15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar). Although these results do not necessarily mean that members of the group II subfamily of sPLA2s specifically release AAin vivo, since exogenously added radiolabeled fatty acids are often incorporated into separate phospholipid fractions and do not always reflect the intracellular movement of endogenous fatty acids, direct comparisons between distinct groups of sPLA2s strongly suggest that they act on different phospholipid pools; members of the group II subfamily of sPLA2s may exert their actions in [3H]AA-enriched microdomains (43Murakami M. Kambe T. Shimbara S. Yamamoto S. Kuwata H. Kudo I. J. Biol. Chem. 1999; 274: 29927-29936Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar), while sPLA2-X may function in other compartments into which both [3H]AA and [3H]OA are equally incorporated.Another remarkable difference among these sPLA2s is their PG-producing capacities. The AA released by sPLA2-X gains access to the PG-biosynthetic pathway with difficulty unless either of the COX isoforms is overexpressed (Figs. 3 and 4). On the other hand, the AA released by the group II subfamily of sPLA2s can be readily metabolized to PGE2 by endogenous COX-2, and as we have reported previously (16Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar), coexpression of sPLA2-IIA or -V and COX-2 increases PGE2 generation further. The characteristics of cells expressing sPLA2-X resembled those of cells expressing iPLA2; both enzymes release fatty acids nonspecifically in a FCS-dependent but not IL-1-dependent manner, and released AA is not metabolized to PGE2 unless COXs are overexpressed (15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 16Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar). Based on an analogy with cells that overexpress intracellular iPLA2(15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 16Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar), which releases fatty acids spontaneously during cell culture, sPLA2-X may have the ability to act as an extracellular phospholipid remodeling PLA2. This is reminiscent of the relationships between cPLA2 and sPLA2s-IIA and -V, which are intracellular and extracellular signaling PLA2s, respectively, that contribute to the stimulus-initiated PG-biosynthetic pathway (15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 16Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar), and between platelet-activating factor-acetylhydrolase II (45Matsuzawa A. Hattori K. Aoki J. Arai H. Inoue K. J. Biol. Chem. 1997; 272: 32315-32320Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar) and plasma platelet-activating factor-acetylhydrolase (46Tjoelke L.W. Wilder C. Eberhardt C. Stafforini D.M. Dietsch G. Schimpf B. Hooper S. Le Trong H. Cousens L.S. Zimmerman G.A Yamada Y. McIntyre T.M. Prescott S.M. Gray P.W. Nature. 1995; 374: 549-553Crossref PubMed Scopus (472) Google Scholar), which act, respectively, as intracellular and extracellular anti-inflammatory and antioxidant PLA2 isozymes.In an effort to clarify the mechanism for different action of these sPLA2s, we found that the heparin-binding sPLA2s have the ability to enhance IL-1-initiated COX-2 expression (Fig. 3 B). Site-directed mutagenesis as well as pharmacological evidence suggests that this property depends on their cell surface heparan sulfate proteoglycan-binding capacity. In contrast, the heparin-nonbinding sPLA2-X did not appreciably increase COX-2 expression. Thus, the COX-2-inducing ability of the heparin-binding sPLA2s apparently contributes to their efficient functional coupling with the delayed PG-biosynthetic response. Suppression of the heparin-binding sPLA2-mediated COX-2 induction by a COX-2 inhibitor implies that certain COX-2 metabolites are involved in this process in an autocrine manner. This appears to be in line with the recent report that the COX-2 promoter contains an element recognized by the peroxisome proliferator-activated receptors, which are activated by fatty acid derivatives including eicosanoids (47Meade E.A. McIntyre T.M. Zimmerman G.A. Prescott S.M. J. Biol. Chem. 1999; 274: 8328-8334Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). However, the finding that PGs alone are insufficient to produce optimal COX-2 expression in 293 cells suggests that some other signals produced by particular heparin-binding sPLA2s, such as sPLA2 receptor-mediated signaling (41Lambeau G. Ancian P. Barhanin J. Lazdunski M. J. Biol. Chem. 1994; 269: 1575-1578Abstract Full Text PDF PubMed Google Scholar, 42Hernandez M. Burillo S.L. Crespo M.S. Nieto M.L. J. Biol. Chem. 1998; 273: 606-612Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar) or heparan sulfate proteoglycan-dependent process (15Murakami M. Shimbara S. Kambe T. Kuwata H. Winstead M.V. Tischfield J.A. Kudo I. J. Biol. Chem. 1998; 273: 14411-14423Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 16Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, 20Murakami M. Nakatani Y. Kudo I. J. Biol. Chem. 1996; 271: 30041-30051Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 43Murakami M. Kambe T. Shimbara S. Yamamoto S. Kuwata H. Kudo I. J. Biol. Chem. 1999; 274: 29927-29936Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar), are required.Based on these observations, we speculated that the poor coupling of sPLA2-X with endogenous COX-2-dependent PG production, despite its efficient AA-releasing ability, may be largely due to its failure to increase COX-2 expression. This idea is supported by the finding that forcible expression of COXs allowed the functional association of sPLA2-X with PG biosynthesis to be bypassed. In this situation, sPLA2-X, like other signaling PLA2s (16Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar), is coupled with overexpressed COX-1 and COX-2 in A23187-induced immediate, and with COX-2 in FCS-induced delayed, PGE2 generation. It is therefore likely that sPLA2-X can act as an extracellular signaling PLA2 in cells that properly express COXs. As sPLA2-X is expressed in tissues related with inflammatory responses (26Cupillard L. Koumanov K. Mattei M.-G. Lazdunski M. Lambeau G. J. Biol. Chem. 1997; 272: 15745-15752Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar), in which high levels of COX-2 are induced, it would be of interest to investigate whether sPLA2-X contributes to PG production during inflammation.It has been proposed that the transbilayer movement of anionic phospholipids, the preferred substrates for the group II subfamily of sPLA2s, to the external surface of the plasma membrane may be one of the mechanisms underlying increased cellular sensitivity to these enzymes (36Kudo I. Murakami M. Hara S. Inoue K. Biochim. Biophys. Acta. 1993; 1170: 217-231Crossref PubMed Scopus (371) Google Scholar). sPLA2-X efficiently hydrolyzes PC (Fig.1 E), which is present in the outer leaflet of the plasma membrane, and this may explain its unique action on the membranes of cells in the absence of a proinflammatory stimulus. This speculation is consistent with a recent report indicating that the V3W mutant of sPLA2-IIA, which possesses a dramatically increased ability to hydrolyze PC vesicles, liberated AA from resting cell membranes as efficiently as sPLA2-IB (48Baker S.F. Othman R. Wilton D.C. Biochemistry. 1998; 37: 13203-13211Crossref PubMed Scopus (86) Google Scholar) and that native sPLA2-X, an isozyme capable of hydrolyzing PC, posses" @default.
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