A Novel Group of Phospholipase A2s Preferentially Expressed in Type 2 Helper T Cells

Abstract

We report a novel phospholipase A2 (PLA2), group XII (GXII) PLA2, distinct from other cysteine-rich groups with a catalytic histidine motif, by its 20-kDa size and distribution of the 14 cysteine residues within the protein. Alternative spliced forms with distinct subcellular localization, designated GXII-1 and GXII-2, were identified by reverse transcription-polymerase chain reaction. Importantly, GXII PLA2s, in particular GXII-2 PLA2, and group V PLA2, but not group X PLA2, were selectively expressed in murine type 2 helper T (Th2) clones and in vitro differentiated mouse CD4 Th2 cells as compared with type 1 helper T clones and cells. Stimulation with anti-CD3 appreciably up-regulated expression of GXII PLA2s and group V PLA2 by steady state analysis of the Th2 cells as compared with type 1 helper T cells. These results suggest that group XII and group V PLA2s might participate in helper T cell immune response through release of immediate second signals and generation of downstream eicosanoids.AY007381AY007382 We report a novel phospholipase A2 (PLA2), group XII (GXII) PLA2, distinct from other cysteine-rich groups with a catalytic histidine motif, by its 20-kDa size and distribution of the 14 cysteine residues within the protein. Alternative spliced forms with distinct subcellular localization, designated GXII-1 and GXII-2, were identified by reverse transcription-polymerase chain reaction. Importantly, GXII PLA2s, in particular GXII-2 PLA2, and group V PLA2, but not group X PLA2, were selectively expressed in murine type 2 helper T (Th2) clones and in vitro differentiated mouse CD4 Th2 cells as compared with type 1 helper T clones and cells. Stimulation with anti-CD3 appreciably up-regulated expression of GXII PLA2s and group V PLA2 by steady state analysis of the Th2 cells as compared with type 1 helper T cells. These results suggest that group XII and group V PLA2s might participate in helper T cell immune response through release of immediate second signals and generation of downstream eicosanoids.AY007381AY007382 phospholipase A2 group cyclooxygenase helper T interleukin prostaglandin murine baby hamster kidney reverse transcription-polymerase chain reaction green fluorescent protein hemagglutinin open reading frame human The family of phospholipase A2(PLA2)1 enzymes is defined by the enzymatic activities of its members, which hydrolyze the sn-2 ester bond of phospholipids to release free fatty acids (1Dennis E.A. Trends Biochem. Sci. 1997; 22: 1-2Abstract Full Text PDF PubMed Scopus (754) Google Scholar). Based on their protein structure and biochemical properties, mammalian PLA2 enzymes can be divided into several classes: low molecular weight secretory; 85-kDa cytosolic; selective acetyl hydrolases of platelet-activating factor; and calcium-independent PLA2. Thus far, eight low molecular weight mammalian PLA2 enzymes have been described including group (G) IB, five GII enzymes, GV, and GX (2Murakami M. Kudo I. Umeda M. Matsuzawa A. Takeda M. Komada M. Fujimori Y. Takahashi K. Inoue K. J. Biochem. ( Tokyo ). 1992; 111: 175-181Crossref PubMed Scopus (71) Google Scholar, 3Valentin E. Koduri R.S. Scimeca J.C. Carle G. Gelb M.H. Lazdunski M. Lambeau G. J. Biol. Chem. 1999; 274: 19152-19160Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 4Cupillard 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, 5Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar). 2A comprehensive abbreviation system for the various mammalian low molecular weight PLA2s is used. Each low molecular weight PLA2 is abbreviated, with a lowercase letter indicating the low molecular weight PLA2species (m and h for mouse and human, respectively), followed by uppercase letters identifying the low molecular weight PLA2group.2A comprehensive abbreviation system for the various mammalian low molecular weight PLA2s is used. Each low molecular weight PLA2 is abbreviated, with a lowercase letter indicating the low molecular weight PLA2species (m and h for mouse and human, respectively), followed by uppercase letters identifying the low molecular weight PLA2group. Each low molecular weight PLA2 is 13–15 kDa in size and contains a signal peptide and 12–14 cysteine residues, the positions and spacing of which are conserved among the low molecular weight PLA2members (6Tischfield J.A. J. Biol. Chem. 1997; 272: 17247-17250Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). In addition, an ∼55-kDa mammalian protein containing a region homologous to the 10-kDa bee venom PLA2 has been described (7Valentin E. Ghomashchi F. Gelb M.H. Lazdunski M. Lambeau G. J. Biol. Chem. 2000; 275: 7492-7496Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). Low molecular weight PLA2 enzymes require millimolar Ca2+ for activity and display no specificity for the fatty acid in the sn-2 position of phospholipids (8Murakami M. Kudo I. Inoue K. J. Lipid Mediat. Cell Signal. 1995; 12: 119-130Crossref PubMed Scopus (64) Google Scholar). Cytosolic PLA2, or GIV PLA2, is a large cytosolic enzyme (∼85 kDa), requires only micromolar Ca2+for activity, and is the only cloned PLA2 that displays high selectivity toward arachidonate-containing phospholipids (9Leslie C.C. J. Biol. Chem. 1997; 272: 16709-16712Abstract Full Text Full Text PDF PubMed Scopus (738) Google Scholar, 10Clark J.D. Schievella A.R. Nalefski E.A. Lin L.L. J. Lipid Mediat. Cell Signal. 1995; 12: 83-117Crossref PubMed Scopus (425) Google Scholar). The hematopoietic calcium-independent PLA2, or GVI PLA2, is an 85-kDa cytosolic enzyme (11Balsinde J. Dennis E.A. J. Biol. Chem. 1997; 272: 16069-16072Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar). In addition to the absence of a calcium requirement, the hematopoietic calcium-independent PLA2 contains eight ankyrin motifs that are not found in any other PLA2 (12Tang J. Kriz R.W. Wolfman N. Shaffer M. Seehra J. Jones S.S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar). Groups IV and VI and the platelet-activating factor acetyl hydrolases (GVII and GVIII) exhibit a catalytic serine, whereas the cysteine-rich, low molecular weight groups utilize a catalytic histidine (13Six D.A. Dennis E.A. Biochim. Biophys. Acta. 2000; 1488: 1-19Crossref PubMed Scopus (1196) Google Scholar). GIV PLA2 has been established, by comparison of various hematopoietic cell types derived from mice with a disruption of this gene with those of their normal littermates, as essential for providing arachidonic acid to the downstream enzymes, such as cyclooxygenase (COX) and 5-lipoxygenase, for generation of prostanoids and leukotrienes (14Bonventre J.V. Huang Z. Taheri M.R. O'Leary E. Li E. Moskowitz M.A. Sapirstein A. Nature. 1997; 390: 622-625Crossref PubMed Scopus (755) Google Scholar, 15Uozumi N. Kume K. Nagase T. Nakatani N. Ishii S. Tashiro F. Komagata Y. Maki K. Ikuta K. Ouchi Y. Miyazaki J. Shimizu T. Nature. 1997; 390: 618-622Crossref PubMed Scopus (636) Google Scholar, 16Fujishima H. Sanchez Mejia R.O. Bingham III, C.O. Lam B.K. Sapirstein A. Bonventre J.V. Austen K.F. Arm J.P. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 4803-4807Crossref PubMed Scopus (166) Google Scholar). GV PLA2, although non-selective as to the sn-2 fatty acid, has been implicated as a supporting enzyme for prostanoid biosynthesis in cell systems by the kinetics of transcript induction and effects of generic inhibitors for several related groups (17Balsinde J. Shinohara H. Lefkowitz L.J. Johnson C.A. Balboa M.A. Dennis E.A. J. Biol. Chem. 1999; 274: 25967-25970Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 18Shinohara H. Balboa M.A. Johnson C.A. Balsinde J. Dennis E.A. J. Biol. Chem. 1999; 274: 12263-12268Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar), but definitive evidence awaits cells with gene disruption. GIIA PLA2, a secretory granule-stored species, has been shown to augment arachidonic acid release by an extracellular membrane action that can be active site-dependent or mediated by cell activation through lectin-like receptors (19Copic A. Vucemilo N. Gubensek F. Krizaj I. J. Biol. Chem. 1999; 274: 26315-26320Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 20Cupillard L. Mulherkar R. Gomez N. Kadam S. Valentin E. Lazdunski M. Lambeau G. J. Biol. Chem. 1999; 274: 7043-7051Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). In addition to these downstream eicosanoid mediators, there are metabolites with gene-inducing functions via interaction with the intracellular receptors of the peroxisome proliferator-activated receptor family (21Forman B.M. Tontonoz P. Chen J. Brun R.P. Spiegelman B.M. Evans R.M. Cell. 1995; 83: 803-812Abstract Full Text PDF PubMed Scopus (2701) Google Scholar, 22Kliewer S.A. Lenhard J.M. Willson T.M. Patel I. Morris D.C. Lehmann J.M. Cell. 1995; 83: 813-819Abstract Full Text PDF PubMed Scopus (1849) Google Scholar). Finally, both released arachidonic acid and the concomitantly generated lysophospholipid have second messenger functions (23Berk P.D. Stump D.D. Mol. Cell. Biochem. 1999; 192: 17-31Crossref PubMed Google Scholar, 24Moolenaar W.H. Kranenburg O. Postma F.R. Zondag G.C. Curr. Opin. Cell Biol. 1997; 9: 168-173Crossref PubMed Scopus (472) Google Scholar, 25Balsinde J. Balboa M.A. Dennis E.A. J. Biol. Chem. 1997; 272: 29317-29321Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). None of the available information reveals a particular T cell distribution for any PLA2 group; nor do the limited examples of gene disruption, GIV and GIIA, provide evidence of an anomaly in the adaptive immune response (14Bonventre J.V. Huang Z. Taheri M.R. O'Leary E. Li E. Moskowitz M.A. Sapirstein A. Nature. 1997; 390: 622-625Crossref PubMed Scopus (755) Google Scholar, 15Uozumi N. Kume K. Nagase T. Nakatani N. Ishii S. Tashiro F. Komagata Y. Maki K. Ikuta K. Ouchi Y. Miyazaki J. Shimizu T. Nature. 1997; 390: 618-622Crossref PubMed Scopus (636) Google Scholar, 26Kennedy B.P. Payette P. Mudgett J. Vadas P. Pruzanski W. Kwan M. Tang C. Rancourt D.E. Cromlish W.A. J. Biol. Chem. 1995; 270: 22378-22385Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar, 27MacPhee M. Chepenik K.P. Liddell R.A. Nelson K.K. Siracusa L.D. Buchberg A.M. Cell. 1995; 81: 957-966Abstract Full Text PDF PubMed Scopus (525) Google Scholar). Several lines of evidence suggest that the PLA2/COX/prostaglandin cascade might play a critical role in regulating the differentiation and function of helper T cells. CD4+ helper T cells can be divided into two functional subsets based on their secreted cytokines (28Mosmann T.R. Sad S. Immunol. Today. 1996; 17: 138-146Abstract Full Text PDF PubMed Scopus (3311) Google Scholar, 29Abbas A.K. Murphy K.M. Sher A. Nature. 1996; 383: 787-793Crossref PubMed Scopus (3833) Google Scholar). Type 1 helper T (Th1) cells secrete interferon-γ and IL-2 and are responsible for delayed type hypersensitivity and eradication of intracellular microorganisms. Type 2 helper T (Th2) cells produce cytokines such as IL-4 and IL-13, which enhance the production of IgE antibodies involved in allergic responses, and IL-5, which promotes the maturation of eosinophils. Furthermore, IL-4 regulates FcεRI expression of human mast cells, whereas IL-5 is comitogenic with stem cell factor for their mucosal expansion (30Bischoff S.C. Sellge G. Lorentz A. Sebald W. Raab R. Manns M.P. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 8080-8085Crossref PubMed Scopus (195) Google Scholar). There is evidence that prostaglandin E2(PGE2), a metabolite of the cyclooxygenase pathway, selectively promotes the differentiation of Th2 cells (31Hilkens C.M. Snijders A. Snijdewint F.G. Wierenga E.A. Kapsenberg M.L. Eur. Respir. J. 1996; 22 (suppl.): 90-94Google Scholar). Production of IL-2 and interferon-γ by short term peripheral blood lymphocyte cultures and by long term Th clones is inhibited by PGE2 in a dose-dependent fashion, whereas IL-4 and IL-5 production is enhanced (32Snijdewint F.G. Kalinski P. Wierenga E.A. Bos J.D. Kapsenberg M.L. J. Immunol. 1993; 150: 5321-5329PubMed Google Scholar, 33Demeure C.E. Yang L.P. Desjardins C. Raynauld P. Delespesse G. Eur. J. Immunol. 1997; 27: 3526-3531Crossref PubMed Scopus (166) Google Scholar). Naı̈ve human CD4+ T cells stimulated with anti-CD3 in the presence of PGE2 display a Th2 phenotype, which is maintained upon restimulation in the absence of PGE2 (34Katamura K. Shintaku N. Yamauchi Y. Fukui T. Y. M. K. J. Immunol. 1995; Google Scholar). Furthermore, PGE2 can of the IL-2 gene but not the IL-4 gene in human T cells F. J. 1993; PubMed Scopus Google Scholar, F. Cell. Immunol. 1996; PubMed Scopus Google Scholar). In addition to its on the of in T cells, PGE2 the release of the from cells, such as cells E. T. K. Y. U. J. Immunol. 2000; PubMed Scopus Google Scholar, P. C.M. Kapsenberg M.L. J. Immunol. Google Scholar), and the expression of the receptor in Th cells K. R.A. J. Immunol. Google Scholar). the mast prostanoid species, has been to the of Th2 prostaglandin is expressed in human Th2 but not cells. The up-regulated expression of hematopoietic prostaglandin and expression of with in the production of by Th2 cells K. K. K. M. S. K. J. Immunol. 2000; PubMed Scopus Google Scholar). mice in the have Th2 and in a of allergic T. M. H. Takahashi Y. T. K. Y. T. F. Y. N. Y. N. K. A. Y. H. S. 2000; PubMed Scopus Google Scholar). report the molecular of a novel PLA2, designated group XII PLA2 which contains two spliced GXII-1 and murine GXII-1 PLA2 and GXII-2 PLA2 a PLA2 catalytic and are cysteine-rich, although the position and spacing of the cysteine residues are from those in other The enzymatic activity of PLA2 is and in low millimolar Importantly, PLA2, in particular PLA2, is expressed in Th2 cells, is upon through the T cell GXII PLA2 is novel in its 20-kDa distribution of cysteine residues, and expression in Th2 cells. Th2 and and murine and were maintained in with and from The murine maintained in with and human IL-2 Th clones were stimulated with anti-CD3 for h The cell is a baby hamster kidney cell maintained in with cells and cells were from and from mice by CD4 and to the cells were stimulated in vitro with anti-CD3 1 in the presence of or h IL-2 to In addition, IL-4 or into Th2 or cells were and with h cells were for antibodies were from The cells were stimulated with and for h acid residues of PLA2 cloned into the and of The and the were to the of the of the cells with of containing for and with 1 for 2 h to PLA2 protein. The cells were with of protein The were with of containing and for The were with 1 of The were in of containing The were by 1 of containing and or 1 h for by 2 of for h The PLA2 contains an and is as by PLA2 activity by the of to acid a of PLA2 or an of a concomitantly of cells to a of containing and for The reaction by the addition of of acid in and in a or cells were and by the to the derived from various from of on a to a and with in the The were the PLA2, the PLA2, and the by the to the of reaction. The of in were as and and a of PLA2 and PLA2, were cloned into in frame with the of The expression and were to cells by to the The cells were on h with for with in for 2 and The PLA2 cloned into the of the the acid residues of PLA2, with a an The and an expression for were to cells M.R. J. A. R. 1996; 274: PubMed Scopus Google Scholar). The cells were and as described The cells were with with of with and with In the of a Th2 cell a that the region of the to an novel analysis that the novel an open reading frame of acid residues, containing a signal peptide its and a conserved for the catalytic of low molecular weight PLA2 In addition, the 14 cysteine residues, to the GIIA PLA2 protein. the position and spacing of the cysteine residues in this novel were distinct from those of other low molecular weight although this contains cysteine residues that are of and the cysteine residues to and which are found in the mammalian low molecular weight The position and spacing of cysteine residues in this novel are from those of other PLA2s, such as and (13Six D.A. Dennis E.A. Biochim. Biophys. Acta. 2000; 1488: 1-19Crossref PubMed Scopus (1196) Google Scholar). novel a calcium for low molecular weight PLA2s Furthermore, its molecular is which is that of the low molecular weight PLA2s, which are These results that the a novel of the PLA2 group PLA2 We the with the and identified several human expressed clones the human GXII-1 PLA2 which is homologous to the PLA2 of the with the PLA2 that the a derived from human Furthermore, a which contains a histidine catalytic PLA2 and 14 cysteine residues with spacing to that of PLA2, in that GXII PLA2 is In addition to PLA2, identified two murine expressed clones and an open reading in which the acid residues of PLA2, including the signal were with a novel acid of residues a distinct related open reading derived from and not any signal peptide and might an spliced of this open reading frame designated murine group PLA2 PLA2 has functional phospholipase A2 catalytic activity, expressed an protein and the protein to as described The of the protein to hydrolyze arachidonic acid in position of PLA2 activity in calcium not The kinetics of release of arachidonic acid of enzyme from to 2 and a activity of of to other low molecular weight PLA2s, the PLA2 contains a signal peptide its that PLA2 might be a secreted protein or a protein. the subcellular of both PLA2 and PLA2, with and the in cells. shown in PLA2 a with to the in cells. The of PLA2 an PLA2 of the expression a and an M.R. J. A. R. 1996; 274: PubMed Scopus Google Scholar), to the of cells. In to PLA2, of a from that of is in with the absence of a signal peptide in PLA2. These results that PLA2 and PLA2 have distinct subcellular there is evidence to suggest that the cascade regulates the differentiation and function of helper T cells, the expression of PLA2s among various Th clones by analysis a to both PLA2 and PLA2. shown in the expression of PLA2s in Th2 such as and and upon with In the clones expressed low of PLA2s, which were anti-CD3 transcript in Th2 Furthermore, PLA2 expressed low in a cell and in cells that been the Th2 but not the two were by the the presence of forms or of PLA2. were to PLA2 from PLA2 by in to the expression and cell type specificity of both forms of PLA2. shown in the expression kinetics and cell type specificity of both PLA2 and PLA2, in particular PLA2, as by are to those by Importantly, PLA2 is expressed in stimulated normal but not or cells In to its expression among the Th cell PLA2 be in a of and PLA2 were only in to a in is in with the of the two PLA2 expressed clones described The that an arachidonic PLA2, GIV PLA2, function in with GV PGE2 generation in a mouse H. Balboa M.A. Johnson C.A. Balsinde J. Dennis E.A. J. Biol. Chem. 1999; 274: 12263-12268Abstract Full Text Full Text PDF PubMed Scopus (143) Google and for production by mouse mast cells Tischfield J.A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google an of the expression of GV PLA2 in Th cells. We the analysis to PLA2 or PLA2. shown in the expression of PLA2 in stimulated Th2 cells but not in cells, whereas the expression of PLA2 and Th2 cells. The Th2 expression of PLA2 by analysis Th shown in PLA2 expressed a low in cells its expression within h anti-CD3 In no expression of PLA2 in cells have described the molecular and of a novel PLA2 designated group the generic of cysteine-rich and a GXII PLA2 this of the no acid other the catalytic histidine motif, with other PLA2 GXII PLA2 is cysteine-rich, the spacing of cysteine residues is distinct from that of other low molecular weight PLA2 GXII PLA2 the calcium of the low molecular weight PLA2 The molecular of PLA2 is which is the 14 kDa of the low molecular weight cysteine-rich PLA2 These and the activity of the PLA2 are in with those of Gelb M.H. Valentin E. Ghomashchi F. Lazdunski M. Lambeau G. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), described mammalian GXII PLA2 this In addition, GXII PLA2 is in species, and spliced and have been GXII PLA2, in particular PLA2, and PLA2 are expressed in Th2 cells within the T cell the of this is the report the expression of PLA2 in Th cells. These suggest an as function of Th2 cells. In of the report that and hematopoietic prostaglandin are expressed in Th2 cells K. K. K. M. S. K. J. Immunol. 2000; PubMed Scopus Google Scholar), is to that the Th2 PLA2s, such as and might be to and hematopoietic prostaglandin in Th2 cells. in Th2 cells, PLA2 and PLA2 might provide arachidonic acid to for generation of that hematopoietic prostaglandin to is by PLA2 in Th2 cells T cell receptor in a to that for induction K. K. K. M. S. K. J. Immunol. 2000; PubMed Scopus Google Scholar). GV PLA2 to the expression of in (17Balsinde J. Shinohara H. Lefkowitz L.J. Johnson C.A. Balboa M.A. Dennis E.A. J. Biol. Chem. 1999; 274: 25967-25970Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). PLA2 is in a in cells. is that the generation of is on the within the cell of the enzymes of their which to in a V PLA2 has been described in with the in mouse mast cells and in a with GIV cytosolic PLA2 to provide arachidonic acid for eicosanoid biosynthesis III, C.O. R.P. R.A. Austen K.F. Arm J.P. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). the PLA2 and PLA2, two Th2 enzymes, are for a functional interaction with the and to which are by hematopoietic prostaglandin to provide and its a metabolite of is of the of the peroxisome proliferator-activated (21Forman B.M. Tontonoz P. Chen J. Brun R.P. Spiegelman B.M. Evans R.M. Cell. 1995; 83: 803-812Abstract Full Text PDF PubMed Scopus (2701) Google Scholar, 22Kliewer S.A. Lenhard J.M. Willson T.M. Patel I. Morris D.C. Lehmann J.M. Cell. 1995; 83: 813-819Abstract Full Text PDF PubMed Scopus (1849) Google Scholar), which shown to be by the Th2 IL-4 and which can gene expression in both T and cells M. Willson T.M. C. Nature. 1999; PubMed Scopus Google Scholar, T. T. L. S.J. J. Immunol. 2000; PubMed Scopus Google Scholar). Furthermore, the report that a second expressed in Th2 cells on Th2 cells, and and is distinct from receptor H. K. O. K. K. Y. M. K. M. S. K. J. PubMed Scopus Google the of an PLA2 and PLA2 might the differentiation and function of Th2 cells of their enzymatic In with this and GIIA PLA2s can by to lectin-like cell receptors 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, A. Vucemilo N. Gubensek F. Krizaj I. J. Biol. Chem. 1999; 274: 26315-26320Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). spliced PLA2, which not any signal low molecular weight PLA2 are secreted or are with cell and in GXII-2 PLA2, a signal be the only within the low molecular weight PLA2 the PLA2 protein is within cells, be that this by of a protein and might not the distribution of the protein. The subcellular of GXII PLA2s can only be by antibodies that the two spliced of GXII such antibodies are not that the subcellular of the PLA2 protein that of PLA2, this the that PLA2 might a in addition to arachidonic acid from cell function of GXII PLA2 be by the analysis of GXII We for and for