Role of Group V Phospholipase A2 in Zymosan-induced Eicosanoid Generation and Vascular Permeability Revealed by Targeted Gene Disruption (2004)

Conclusions regarding the contribution of low molecular weight secretory phospholipase A2 (sPLA2) enzymes in eicosanoid generation have relied on data obtained from transfected cells or the use of inhibitors that fail to discriminate between individual members of the large family of mammalian sPLA2 enzymes. To elucidate the role of group V sPLA2, we used targeted gene disruption to generate mice lacking this enzyme. Zymosan-induced generation of leukotriene C4 and prostaglandin E2 was attenuated ∼50% in peritoneal macrophages from group V sPLA2-null mice compared with macrophages from wild-type littermates. Furthermore, the early phase of plasma exudation in response to intraperitoneal injection of zymosan and the accompanying in vivo generation of cysteinyl leukotrienes were markedly attenuated in group V sPLA2-null mice compared with wild-type controls. These data provide clear evidence of a role for group V sPLA2 in regulating eicosanoid generation in response to an acute innate stimulus of the immune response both in vitro and in vivo, suggesting a role for this enzyme in innate immunity. Conclusions regarding the contribution of low molecular weight secretory phospholipase A2 (sPLA2) enzymes in eicosanoid generation have relied on data obtained from transfected cells or the use of inhibitors that fail to discriminate between individual members of the large family of mammalian sPLA2 enzymes. To elucidate the role of group V sPLA2, we used targeted gene disruption to generate mice lacking this enzyme. Zymosan-induced generation of leukotriene C4 and prostaglandin E2 was attenuated ∼50% in peritoneal macrophages from group V sPLA2-null mice compared with macrophages from wild-type littermates. Furthermore, the early phase of plasma exudation in response to intraperitoneal injection of zymosan and the accompanying in vivo generation of cysteinyl leukotrienes were markedly attenuated in group V sPLA2-null mice compared with wild-type controls. These data provide clear evidence of a role for group V sPLA2 in regulating eicosanoid generation in response to an acute innate stimulus of the immune response both in vitro and in vivo, suggesting a role for this enzyme in innate immunity. The first step in the biosynthesis of eicosanoids is the release of arachidonic acid from cell membrane phospholipids by phospholipase A2. Several classes of phospholipase A2 have been described in mammals (1Six A.D. Dennis E.A. Biochim. Biophys. Acta. 2000; 1488: 1-19Crossref PubMed Scopus (1222) Google Scholar, 2Diaz B.L. Arm J.P. Prostaglandins Leukotrienes Essent. Fatty Acids. 2003; 69: 87-97Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). Cytosolic phospholipase A2 (cPLA2) 1The abbreviations used are: cPLA2, cytosolic phospholipase A2; HBA, Hanks' balanced salt solution containing 0.1% bovine serum albumin; LT, leukotriene; sPLA2, secretory phospholipase A2; PG, prostaglandin; LPS, lipopolysaccharide; RT-PCR, reverse transcription-PCR; Pipes, 1,4-piperazinediethanesulfonic acid; PBS, phosphate-buffered saline; RP-HPLC, reverse-phase high performance liquid chromatography; CysLT1R, cysteinyl leukotriene type 1 receptor. α is an 85-kDa cytosolic enzyme that uses a catalytic serine residue and preferentially cleaves arachidonic acid from cell membrane phospholipids (3Clark J.D. Lin L.L. Kriz R.W. Ramesha C.S. Sultzman L.A. Lin A.Y. Milona N. Knopf J.L. Cell. 1991; 65: 1043-1051Abstract Full Text PDF PubMed Scopus (1465) Google Scholar). The Ca2+-dependent translocation of cPLA2-α from the cytosol to the nuclear envelope (4McNish R.W. Peters-Golden M. Biochem. Biophys. Res. Commun. 1993; 196: 147-153Crossref PubMed Scopus (177) Google Scholar), a prominent site of eicosanoid biosynthesis, is dependent on a Ca2+-dependent lipid binding (C-2) domain. Paralogues of cPLA2-α (cPLA2-β and cPLA2-γ) have been described previously (5Underwood K.W. Sung C. Kriz R.W. Chang X.J. Knopf J.L. Lin L.-L. J. Biol. Chem. 1998; 273: 21926-21932Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 6Pickard R.T. Strifler B.A. Kramer R.M. Sharp J.D. J. Biol. Chem. 1999; 274: 8823-8831Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). cPLA2-β has a Mr of 110,000 and shares 30% identity with cPLA2-α, including a functional C-2 domain. cPLA2-γ has a Mr of 61,000, shares 29% sequence identity with cPLA2-α, lacks a C-2 domain, and is Ca2+-independent. Mammalian low molecular weight secretory phospholipase A2 (sPLA2) enzymes, which are now 10 in number, are characterized by a conserved motif containing a catalytic histidine residue, by their relatively small size of ∼14 kDa, and by their highly disulfide-linked tertiary structures (7Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 23018-23024Abstract Full Text PDF PubMed Google Scholar, 8Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar, 9Cupillard L. Koumanov K. Mattéi M.-G. Lazdunski M. Lambeau G. J. Biol. Chem. 1997; 272: 15745-15752Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 10Valentin 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 (116) Google Scholar, 11Valentin E. Ghomashchi F. Gelb M.H. Lazdunski M. Lambeau G. J. Biol. Chem. 1999; 274: 31195-31202Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 12Gelb M.H. Valentin E. Ghomashchi F. Lazdunski M. Lambeau G. J. Biol. Chem. 2000; 275: 39823-39826Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 13Ho I.C. Arm J.P. Bingham III, C.O. Choi A. Austen K.F. Glimcher L.H. J. Biol. Chem. 2001; 276: 18321-18326Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). They are distinguished from one another by their structures, their biochemical properties, and their tissue distribution. Calcium-independent phospholipase A2 enzymes have been described in myocardium and in leukocytes (14Gross R.W. J. Lipid Mediat. Cell Signal. 1995; 12: 131-137Crossref PubMed Scopus (17) Google Scholar, 15Ackermann E.J. Dennis E.A. J. Biol. Chem. 1994; 269: 9227-9233Abstract Full Text PDF PubMed Google Scholar). They have been implicated in membrane remodeling, regulation of store operated calcium channels, apoptosis, and release of arachidonic acid. The fourth group of phospholipase A2 enzymes comprises the acetyl hydrolases of platelet activating factor (16Tjoelker L.W. Stafforini D.M. Biochim. Biophys. Acta. 2000; 1488: 102-123Crossref PubMed Scopus (150) Google Scholar). Given the complexity and size of the phospholipase A2 family, targeted gene disruption is a suitable approach to elucidating the role(s) of individual enzymes and proved fruitful in determining the role of cPLA2-α in regulating eicosanoid biosynthesis. Disruption of the gene encoding cPLA2-α led to almost complete abrogation of the rapid generation of prostaglandin (PG) E2, leukotriene (LT) C4, and LTB4 from peritoneal macrophages in response to A23187 and a more delayed generation of PGE2 in response to lipopolysaccharide (LPS) (17Uozumi 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 (644) Google Scholar, 18Bonventre J.V. Huang Z. Taheri M.R. O'Leary E. Li E. Moskowitz M.A. Sapirstein A. Nature. 1997; 390: 622-625Crossref PubMed Scopus (760) Google Scholar). Separate studies demonstrated a marked attenuation of the release of labeled arachidonic acid from cPLA2-α-null peritoneal macrophages in response to zymosan, A23187, phorbol myristate acetate, and okadaic acid (19Gijon M.A. Spencer D.M. Siddiq A.R. Bonventre J.V. Leslie C.C. J. Biol. Chem. 2000; 275: 20146-20156Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar) and the critical role of this enzyme in immediate and delayed phases of eicosanoid generation by mouse bone marrow culture-derived mast cells (20Fujishima H. Sanchez Meija R. 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 (169) Google Scholar, 21Nakatani N. Uozumi N. Kume K. Murakami M. Kudo I. Shimizu T. Biochem. J. 2000; 352: 311-317Crossref PubMed Scopus (52) Google Scholar). Whereas these data demonstrate the essential function of cPLA2-α in supplying arachidonic acid for leukotriene and prostaglandin biosynthesis, several lines of evidence have suggested that low molecular weight sPLA2 enzymes amplify the actions of cPLA2-α in eicosanoid generation. Transfection of HEK293 cells with the heparin-binding group IIA sPLA2, group V sPLA2, or group IID sPLA2 amplified the cPLA2-α-dependent release of arachidonic acid and PGE2 generation in response to A23187 or to LPS and interleukin-1β (22Murakami 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 (340) Google Scholar, 23Murakami M. Koduri R.S. Enomoto A. Shimbara S. Seki M. Yoshihara K. Singer A. Valentin E. Ghomashchi F. Lambeau G. Gelb M.H. Kudo I. J. Biol. Chem. 2001; 276: 10083-10096Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). The action of these enzymes was attributed to their ability to bind to glypican in caveoli, leading to internalization and co-localization with prostaglandin endoperoxide synthase enzymes (22Murakami 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 (340) Google Scholar). Similarly, adenoviral transfection of group V sPLA2 or group IIA sPLA2 into mouse mesangial cells amplified release of arachidonic acid. was in and in cPLA2-α-null cells Sapirstein A. C.C. A. Bonventre J.V. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). macrophages were with LPS for 1 and with platelet activating was release of labeled arachidonic acid J. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar). with inhibitors and with suggested that the release of arachidonic acid was dependent cPLA2-α, the release was dependent group V sPLA2, which was dependent the action of cPLA2-α M.A. J. Winstead M.V. Tischfield J.A. Dennis E.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (198) Google Scholar, J. Dennis E.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the LPS a delayed phase of arachidonic acid release and prostaglandin endoperoxide PGE2 generation. cPLA2-α and group V sPLA2 were in to the response to LPS and platelet activating of cPLA2-α led to of group V sPLA2 that in prostaglandin endoperoxide H. M.A. J. Dennis E.A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). The data low molecular weight sPLA2 enzymes in eicosanoid generation have relied on transfection or and The with to the of a sPLA2, fail to the role of the enzymes. The have J. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar, J. Dennis E.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), to discriminate between individual low molecular weight phospholipase A2 enzymes J.A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar), or data J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, III, C.O. Murakami M. H. Austen K.F. Arm J.P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). To the role of group V vivo and in we have mice with targeted disruption of the gene encoding this enzyme. enzymes were from serum zymosan and were from Disruption of the for V used a group V sPLA2 III, C.O. Austen K.F. Arm J.P. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar) to a mouse in of the group V sPLA2 of was and used to a in which the fourth was with and with a gene that a to of the histidine residue essential for the catalytic function of the sPLA2 enzymes E.A. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar) and to a and V are gene was a site of the cells were transfected with the with of the were in and to and by cell for disruption of the group V sPLA2 gene were into from mice and to the of that were for and cells were by mice and with were of the from cell were to mice were for of the of group V sPLA2 by of from from this generation of group V mice were and their group V sPLA2-null and group V were used in from mouse was with or in of to and with a of from the of the group V sPLA2 gene that the were in and was to the of from were in of to and with a the of group V sPLA2 described previously J.P. C. Austen K.F. J. 1997; Google Scholar). of for group V sPLA2 was by of was reverse reverse and the for for 1 of the were used in a with the that the in and reverse in were a step for by of for for and for by a step for 10 for were used a were on and with of V sPLA2 peritoneal of mice were with of Pipes, 1 1 cells were on in tissue in of bovine and and with cells were by with were with in phosphate-buffered for in Hanks' balanced salt solution or containing 0.1% bovine serum with in for 10 and with were in containing serum for 1 were with group V sPLA2 III, C.O. Austen K.F. Arm J.P. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar) in for with HBA, and for 1 with and were with HBA, in and with a with a and of peritoneal of mice by were with of containing bovine and 10 in cells in of bovine and were in individual of a tissue and for with cells were by with cells from mouse were and to the of which between group V sPLA2-null cells and wild-type of containing 0.1% serum were to and cells were in a and with zymosan Leslie C.C. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar). were for of cysteinyl leukotrienes and PGE2 by were for cysteinyl leukotriene by reverse phase high performance liquid Zymosan-induced mouse an injection of in into the injection of 1 of zymosan in into the peritoneal A. Austen K.F. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to the mice were by and the peritoneal was with of The peritoneal was for and the of the was to of of and of for were to the on for and for 10 The were by in and and for cysteinyl leukotriene by of leukotrienes were by described previously A. Austen K.F. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Meija Lam B.K. Arm J.P. J. Cell Biol. 2000; PubMed Scopus Google Scholar). were to a with a of acid injection of the the was a of 1 with a to of and was to and this for an The was The for and were and of cysteinyl leukotrienes were from the of the of leukotriene to the of the for the in are and between were of V generate mice lacking group V sPLA2, we used targeted gene of wild-type for group V sPLA2 of and with and of from with disruption of the group V sPLA2 gene and wild-type with with and from enzyme of wild-type and The mouse is in for group V sPLA2 J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar). To that of the for group V sPLA2 led to of was from the of mice to the and for group V sPLA2 by and from the of wild-type mice and mice a of on from mice wild-type for the group V sPLA2 gene of and a of the size on The that the in group V sPLA2-null were is by of wild-type a of the size and a that on was to of described previously for group V sPLA2 N. Ghomashchi F. E. Singer A. N. R. C. Lambeau G. Arm J. Tischfield J. Gelb M.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of from group V sPLA2-null to a in the of of group V sPLA2 in peritoneal macrophages from group V sPLA2-null peritoneal macrophages from wild-type for group V sPLA2 with to the we previously for mouse bone marrow culture-derived mast cells III, C.O. Austen K.F. Arm J.P. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). of mice for the of group V sPLA2 of and mice with a of of the V sPLA2-null mice were to of that group V sPLA2 is for and of macrophages have been used to eicosanoid generation (17Uozumi 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 (644) Google Scholar, 18Bonventre J.V. Huang Z. Taheri M.R. O'Leary E. Li E. Moskowitz M.A. Sapirstein A. Nature. 1997; 390: 622-625Crossref PubMed Scopus (760) Google Scholar, M.A. Spencer D.M. Siddiq A.R. Bonventre J.V. Leslie C.C. J. Biol. Chem. 2000; 275: 20146-20156Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar, M.A. Spencer D.M. Leslie C.C. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar), and group V sPLA2 are an of the innate immune They to of zymosan from with eicosanoid generation in vitro Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar), and in vivo of zymosan to the peritoneal an response with plasma exudation that is dependent in on the release of cysteinyl leukotrienes the cysteinyl leukotriene type 1 A. Austen K.F. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. A. Austen K.F. Lam B.K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). eicosanoid generation in peritoneal macrophages from group V sPLA2-null mice in vitro and cysteinyl leukotriene generation and plasma in response to intraperitoneal injection of zymosan in Zymosan-induced by of group V sPLA2-null and wild-type macrophages with zymosan cysteinyl leukotriene and PGE2 generation leukotriene generation zymosan PGE2 generation with a response and cysteinyl leukotriene generation and PGE2 generation were attenuated of zymosan in group V sPLA2-null peritoneal macrophages compared with wild-type with in the of the and leukotriene generation in response to zymosan was attenuated in group V sPLA2-null macrophages cells compared with wild-type PGE2 generation in response to zymosan was attenuated in group V sPLA2-null macrophages cells compared with wild-type the identity of the cysteinyl leukotrienes in the cell with to or and the attenuation of generation in group V sPLA2-null macrophages compared with wild-type macrophages of eicosanoid generation in group V sPLA2-null peritoneal macrophages was demonstrated for macrophages obtained from mice from cell These data demonstrate a role for group V sPLA2 in eicosanoid generation by peritoneal was release of both and PGE2 from group V sPLA2-null macrophages in response to demonstrated complete abrogation of the release of arachidonic acid in response to zymosan in peritoneal macrophages from mice lacking cPLA2-α (19Gijon M.A. Spencer D.M. Siddiq A.R. Bonventre J.V. Leslie C.C. J. Biol. Chem. 2000; 275: 20146-20156Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar). with this an for cPLA2-α in eicosanoid generation by peritoneal macrophages and an role for group V is with the obtained in HEK293 the function of transfected group V sPLA2 in supplying arachidonic acid for eicosanoid generation was by of cPLA2-α (22Murakami 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 (340) Google Scholar). of mouse mesangial adenoviral transfection with group V sPLA2 arachidonic acid release in response to by cells obtained from mice from cPLA2-α-null mice Sapirstein A. C.C. A. Bonventre J.V. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The by which group V sPLA2 the essential function of cPLA2-α is and is the of The of group V sPLA2 and with cPLA2-α in the release of arachidonic acid has been demonstrated in the mouse cell these cells were labeled with acid for with LPS for 1 and with was a release of labeled arachidonic acid J. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar). the first which was complete arachidonic acid was and the in the release of labeled arachidonic acid the 10 with inhibitors and with demonstrated that the release of arachidonic acid was dependent cPLA2-α, the release was dependent group V sPLA2 M.A. J. Winstead M.V. Tischfield J.A. Dennis E.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (198) Google Scholar). The action of cPLA2-α for the function of group V sPLA2 J. Dennis E.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the LPS a delayed phase of arachidonic acid release and prostaglandin endoperoxide PGE2 generation H. M.A. J. Dennis E.A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). cPLA2-α and group V sPLA2 were in to the response to LPS and of cPLA2-α led to of group V sPLA2 which in prostaglandin endoperoxide of arachidonic acid release in macrophages was described in response to zymosan J. M.A. Dennis E.A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). the Ca2+-dependent of cPLA2-α, which an immediate and release of arachidonic acid that was by an of cPLA2-α, and by an of group V sPLA2 J. M.A. Dennis E.A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). with LPS the response to zymosan, an in release of arachidonic acid that was by group V sPLA2 the response to a role for group V sPLA2 in peritoneal macrophages with zymosan in the of LPS The between data and obtained with the cell to the of cells or to the that release of arachidonic acid in response to zymosan was in the of this cell J. M.A. Dennis E.A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar) to the that cells have low of arachidonic acid compared with of mouse macrophages J. Dennis E.A. J. Biochem. PubMed Scopus Google Scholar). Zymosan-induced of the encoding synthase Y. A. Austen K.F. Lam B.K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) and of A. Austen K.F. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), the contribution of the cysteinyl CysLT1R, to plasma exudation in cysteinyl leukotriene generation and plasma exudation of in group V sPLA2-null and wild-type mice in response to intraperitoneal injection of a of zymosan A. was a ∼50% attenuation of the of and injection of zymosan in mice lacking group V sPLA2 compared with that in wild-type in plasma exudation was and cysteinyl leukotrienes in the peritoneal intraperitoneal injection of zymosan, was attenuation of plasma was the cysteinyl leukotriene in the previously Y. A. Austen K.F. Lam B.K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), and generation was attenuated in group V sPLA2-null compared with wild-type generation in the peritoneal of mice with zymosan A. V sPLA2-null and wild-type mice were with 1 zymosan A. The cysteinyl leukotriene of the was by described are for and cysteinyl leukotriene generation. was The attenuation of in response to zymosan in group V sPLA2-null mice early is from the in mice lacking synthase or A. Austen K.F. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. A. Austen K.F. Lam B.K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). the attenuated was to 1 intraperitoneal injection of zymosan, and in the to the attenuation of plasma exudation in both of mice was early and was marked and with in group V sPLA2-null mice and a role for Furthermore, the attenuation of cysteinyl leukotriene generation in group V sPLA2-null mice in vivo, in was of cysteinyl leukotriene generation in the of attenuated leukotriene Whereas targeted gene disruption a role for group V sPLA2 in eicosanoid generation by peritoneal macrophages and in plasma the of action of group V sPLA2 are in the of the are with a role for group V sPLA2 in the response to cPLA2-α (22Murakami 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 (340) Google Scholar, Sapirstein A. C.C. A. Bonventre J.V. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Dennis E.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the of this is of group V sPLA2 from the cell with internalization binding to (22Murakami 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 (340) Google Scholar). to the of group V sPLA2 for binding to release of arachidonic acid from cell membrane phospholipids Koduri R. L. A.R. Gelb M.H. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar), described for A.Y. E. O'Leary E. S. Bonventre J.V. A.R. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), group V sPLA2 for action the of these of action the of the enzyme and internalization for action in an or a data prominent for group V sPLA2 The is a prominent for enzymes of eicosanoid biosynthesis, J. Lam B.K. K. R.M. Austen K.F. J. Cell Biol. 1995; Scholar, S. L. J.A. S. Singer J. 1993; PubMed Scopus Google Scholar) or translocation in response to calcium (4McNish R.W. Peters-Golden M. Biochem. Biophys. Res. Commun. 1993; 196: 147-153Crossref PubMed Scopus (177) Google Scholar, Spencer D.M. A. Leslie C.C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. M. E. Gelb M.H. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). group V sPLA2 a for to amplify the of this is the first of mice with targeted disruption of group V studies the of the enzyme in eicosanoid generation both in vitro and in vivo and a role for the enzyme in acute innate immune are to A. and for