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. 1996 May 15;97(10):2233–2241. doi: 10.1172/JCI118664

Expression of human group II PLA2 in transgenic mice results in epidermal hyperplasia in the absence of inflammatory infiltrate.

D S Grass 1, R H Felkner 1, M Y Chiang 1, R E Wallace 1, T J Nevalainen 1, C F Bennett 1, M E Swanson 1
PMCID: PMC507302  PMID: 8636402

Abstract

Group II PLA2 has been implicated in inflammatory processes in both man and other animals and has been shown to be involved in inflammatory conditions, such as arthritis and sepsis. Transgenic mice expressing the human group II PLA2 gene have been generated using a 6.2-kb genomic fragment. These mice express the group II PLA2 gene abundantly in liver, lung, kidney, and skin, and have serum PLA2 activity levels approximately eightfold higher than nontransgenic littermates. The group II PLA2 transgenic mice reported here exhibit epidermal and adnexal hyperplasia, hyperkeratosis, and almost total alopecia. The chronic epidermal hyperplasia and hyperkeratosis seen in these mice is similar to that seen in a variety of dermatopathies, including psoriasis. However, unlike what is seen with these dermatopathies, no significant inflammatory-cell influx was observed in the skin of these animals, or in any other tissue examined. These mice provide an important tool for examining group II PLA2 expression, and for determining the role of group II PLA2 in normal and disease physiology. They serve as an in vivo model for identifying inhibitors of group II PLA2 activity and gene expression.

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Selected References

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  1. Aarsman A. J., de Jong J. G., Arnoldussen E., Neys F. W., van Wassenaar P. D., Van den Bosch H. Immunoaffinity purification, partial sequence, and subcellular localization of rat liver phospholipase A2. J Biol Chem. 1989 Jun 15;264(17):10008–10014. [PubMed] [Google Scholar]
  2. Andersen S., Sjursen W., Laegreid A., Austgulen R., Johansen B. Immunohistologic detection of non-pancreatic phospholipase A2 (type II) in human placenta and its possible involvement in normal parturition at term. Prostaglandins Leukot Essent Fatty Acids. 1994 Jul;51(1):19–26. doi: 10.1016/0952-3278(94)90173-2. [DOI] [PubMed] [Google Scholar]
  3. Arita H., Hanasaki K., Nakano T., Oka S., Teraoka H., Matsumoto K. Novel proliferative effect of phospholipase A2 in Swiss 3T3 cells via specific binding site. J Biol Chem. 1991 Oct 15;266(29):19139–19141. [PubMed] [Google Scholar]
  4. Barrandon Y., Green H. Cell migration is essential for sustained growth of keratinocyte colonies: the roles of transforming growth factor-alpha and epidermal growth factor. Cell. 1987 Sep 25;50(7):1131–1137. doi: 10.1016/0092-8674(87)90179-6. [DOI] [PubMed] [Google Scholar]
  5. Bomalaski J. S., Lawton P., Browning J. L. Human extracellular recombinant phospholipase A2 induces an inflammatory response in rabbit joints. J Immunol. 1991 Jun 1;146(11):3904–3910. [PubMed] [Google Scholar]
  6. Bouclier M., Luginbuhl B., Delamadeleine F., Rossio P., Hensby C. Repeated application of arachidonic acid to the ear of mice: a model of chronic skin inflammation? Agents Actions. 1989 Jan;26(1-2):227–228. doi: 10.1007/BF02126619. [DOI] [PubMed] [Google Scholar]
  7. Chen J., Engle S. J., Seilhamer J. J., Tischfield J. A. Cloning and recombinant expression of a novel human low molecular weight Ca(2+)-dependent phospholipase A2. J Biol Chem. 1994 Jan 28;269(4):2365–2368. [PubMed] [Google Scholar]
  8. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  9. Clark J. D., Lin L. L., Kriz R. W., Ramesha C. S., Sultzman L. A., Lin A. Y., Milona N., Knopf J. L. A novel arachidonic acid-selective cytosolic PLA2 contains a Ca(2+)-dependent translocation domain with homology to PKC and GAP. Cell. 1991 Jun 14;65(6):1043–1051. doi: 10.1016/0092-8674(91)90556-e. [DOI] [PubMed] [Google Scholar]
  10. Clark J. D., Milona N., Knopf J. L. Purification of a 110-kilodalton cytosolic phospholipase A2 from the human monocytic cell line U937. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7708–7712. doi: 10.1073/pnas.87.19.7708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Crowl R. M., Stoller T. J., Conroy R. R., Stoner C. R. Induction of phospholipase A2 gene expression in human hepatoma cells by mediators of the acute phase response. J Biol Chem. 1991 Feb 5;266(4):2647–2651. [PubMed] [Google Scholar]
  12. Davidson F. F., Dennis E. A. Evolutionary relationships and implications for the regulation of phospholipase A2 from snake venom to human secreted forms. J Mol Evol. 1990 Sep;31(3):228–238. doi: 10.1007/BF02109500. [DOI] [PubMed] [Google Scholar]
  13. Davidson F. F., Dennis E. A., Powell M., Glenney J. R., Jr Inhibition of phospholipase A2 by "lipocortins" and calpactins. An effect of binding to substrate phospholipids. J Biol Chem. 1987 Feb 5;262(4):1698–1705. [PubMed] [Google Scholar]
  14. Dennis E. A. Diversity of group types, regulation, and function of phospholipase A2. J Biol Chem. 1994 May 6;269(18):13057–13060. [PubMed] [Google Scholar]
  15. Dennis E. A., Rhee S. G., Billah M. M., Hannun Y. A. Role of phospholipase in generating lipid second messengers in signal transduction. FASEB J. 1991 Apr;5(7):2068–2077. doi: 10.1096/fasebj.5.7.1901288. [DOI] [PubMed] [Google Scholar]
  16. Forster S., Ilderton E., Norris J. F., Summerly R., Yardley H. J. Characterization and activity of phospholipase A2 in normal human epidermis and in lesion-free epidermis of patients with psoriasis or eczema. Br J Dermatol. 1985 Feb;112(2):135–147. doi: 10.1111/j.1365-2133.1985.tb00077.x. [DOI] [PubMed] [Google Scholar]
  17. Forster S., Ilderton E., Summerly R., Yardley H. J. The level of phospholipase A2 activity is raised in the uninvolved epidermis of psoriasis. Br J Dermatol. 1983 Jan;108(1):103–105. doi: 10.1111/j.1365-2133.1983.tb04585.x. [DOI] [PubMed] [Google Scholar]
  18. Grayson D. R., Costa R. H., Darnell J. E. Regulation of hepatocyte-specific gene expression. Ann N Y Acad Sci. 1989;557:243-55, discussion 255-6. doi: 10.1111/j.1749-6632.1989.tb24018.x. [DOI] [PubMed] [Google Scholar]
  19. Green J. A., Smith G. M., Buchta R., Lee R., Ho K. Y., Rajkovic I. A., Scott K. F. Circulating phospholipase A2 activity associated with sepsis and septic shock is indistinguishable from that associated with rheumatoid arthritis. Inflammation. 1991 Oct;15(5):355–367. doi: 10.1007/BF00917352. [DOI] [PubMed] [Google Scholar]
  20. Grönroos J. M., Nevalainen T. J. Increased concentrations of synovial-type phospholipase A2 in serum and pulmonary and renal complications in acute pancreatitis. Digestion. 1992;52(3-4):232–236. doi: 10.1159/000200958. [DOI] [PubMed] [Google Scholar]
  21. Hara S., Kudo I., Chang H. W., Matsuta K., Miyamoto T., Inoue K. Purification and characterization of extracellular phospholipase A2 from human synovial fluid in rheumatoid arthritis. J Biochem. 1989 Mar;105(3):395–399. doi: 10.1093/oxfordjournals.jbchem.a122675. [DOI] [PubMed] [Google Scholar]
  22. Heinrikson R. L., Krueger E. T., Keim P. S. Amino acid sequence of phospholipase A2-alpha from the venom of Crotalus adamanteus. A new classification of phospholipases A2 based upon structural determinants. J Biol Chem. 1977 Jul 25;252(14):4913–4921. [PubMed] [Google Scholar]
  23. Horigome K., Hayakawa M., Inoue K., Nojima S. Selective release of phospholipase A2 and lysophosphatidylserine-specific lysophospholipase from rat platelets. J Biochem. 1987 Jan;101(1):53–61. doi: 10.1093/oxfordjournals.jbchem.a121907. [DOI] [PubMed] [Google Scholar]
  24. Hsu S. M., Raine L., Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981 Apr;29(4):577–580. doi: 10.1177/29.4.6166661. [DOI] [PubMed] [Google Scholar]
  25. Kennedy B. P., Payette P., Mudgett J., Vadas P., Pruzanski W., Kwan M., Tang C., Rancourt D. E., Cromlish W. A. A natural disruption of the secretory group II phospholipase A2 gene in inbred mouse strains. J Biol Chem. 1995 Sep 22;270(38):22378–22385. doi: 10.1074/jbc.270.38.22378. [DOI] [PubMed] [Google Scholar]
  26. Kramer R. M., Hession C., Johansen B., Hayes G., McGray P., Chow E. P., Tizard R., Pepinsky R. B. Structure and properties of a human non-pancreatic phospholipase A2. J Biol Chem. 1989 Apr 5;264(10):5768–5775. [PubMed] [Google Scholar]
  27. Kudo I., Chang H. W., Hara S., Murakami M., Inoue K. Characteristics and pathophysiological roles of extracellular phospholipase A2 in inflamed sites. Dermatologica. 1989;179 (Suppl 1):72–76. doi: 10.1159/000248454. [DOI] [PubMed] [Google Scholar]
  28. Lambeau G., Ancian P., Barhanin J., Lazdunski M. Cloning and expression of a membrane receptor for secretory phospholipases A2. J Biol Chem. 1994 Jan 21;269(3):1575–1578. [PubMed] [Google Scholar]
  29. MacPhee M., Chepenik K. P., Liddell R. A., Nelson K. K., Siracusa L. D., Buchberg A. M. The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell. 1995 Jun 16;81(6):957–966. doi: 10.1016/0092-8674(95)90015-2. [DOI] [PubMed] [Google Scholar]
  30. Margolis B. L., Bonventre J. V., Kremer S. G., Kudlow J. E., Skorecki K. L. Epidermal growth factor is synergistic with phorbol esters and vasopressin in stimulating arachidonate release and prostaglandin production in renal glomerular mesangial cells. Biochem J. 1988 Jan 15;249(2):587–592. doi: 10.1042/bj2490587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Margolis B. L., Holub B. J., Troyer D. A., Skorecki K. L. Epidermal growth factor stimulates phospholipase A2 in vasopressin-treated rat glomerular mesangial cells. Biochem J. 1988 Dec 1;256(2):469–474. doi: 10.1042/bj2560469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mayer R. J., Marshall L. A. New insights on mammalian phospholipase A2(s); comparison of arachidonoyl-selective and -nonselective enzymes. FASEB J. 1993 Feb 1;7(2):339–348. doi: 10.1096/fasebj.7.2.8440410. [DOI] [PubMed] [Google Scholar]
  33. Mizushima H., Kudo I., Horigome K., Murakami M., Hayakawa M., Kim D. K., Kondo E., Tomita M., Inoue K. Purification of rabbit platelet secretory phospholipase A2 and its characteristics. J Biochem. 1989 Apr;105(4):520–525. doi: 10.1093/oxfordjournals.jbchem.a122699. [DOI] [PubMed] [Google Scholar]
  34. Murakami M., Kudo I., Umeda M., Matsuzawa A., Takeda M., Komada M., Fujimori Y., Takahashi K., Inoue K. Detection of three distinct phospholipases A2 in cultured mast cells. J Biochem. 1992 Feb;111(2):175–181. doi: 10.1093/oxfordjournals.jbchem.a123733. [DOI] [PubMed] [Google Scholar]
  35. Nakano T., Arita H. Enhanced expression of group II phospholipase A2 gene in the tissues of endotoxin shock rats and its suppression by glucocorticoid. FEBS Lett. 1990 Oct 29;273(1-2):23–26. doi: 10.1016/0014-5793(90)81042-m. [DOI] [PubMed] [Google Scholar]
  36. Nevalainen T. J., Aho H. J., Peuravuori H. Secretion of group 2 phospholipase A2 by lacrimal glands. Invest Ophthalmol Vis Sci. 1994 Feb;35(2):417–421. [PubMed] [Google Scholar]
  37. Nevalainen T. J., Grönroos J. M., Kallajoki M. Expression of group II phospholipase A2 in the human gastrointestinal tract. Lab Invest. 1995 Feb;72(2):201–208. [PubMed] [Google Scholar]
  38. Nevalainen T. J., Meri K. M., Niemi M. Synovial-type (group II) phospholipase A2 human seminal plasma. Andrologia. 1993 Nov-Dec;25(6):355–358. doi: 10.1111/j.1439-0272.1993.tb02742.x. [DOI] [PubMed] [Google Scholar]
  39. Nevalainen T. J., Märki F., Kortesuo P. T., Grütter M. G., Di Marco S., Schmitz A. Synovial type (group II) phospholipase A2 in cartilage. J Rheumatol. 1993 Feb;20(2):325–330. [PubMed] [Google Scholar]
  40. Nevalainen T. J. Serum phospholipases A2 in inflammatory diseases. Clin Chem. 1993 Dec;39(12):2453–2459. [PubMed] [Google Scholar]
  41. Olivier J. L., Fan Q., Salvat C., Ziari M., Kong L., Mangeney M., Bereziat G. Positive and negative hepatic regulation of the human type II phospholipase A2 gene. Biochemistry. 1994 Jun 14;33(23):7134–7145. doi: 10.1021/bi00189a017. [DOI] [PubMed] [Google Scholar]
  42. Ono T., Tojo H., Kuramitsu S., Kagamiyama H., Okamoto M. Purification and characterization of a membrane-associated phospholipase A2 from rat spleen. Its comparison with a cytosolic phospholipase A2 S-1. J Biol Chem. 1988 Apr 25;263(12):5732–5738. [PubMed] [Google Scholar]
  43. Pruzanski W., Vadas P., Fornasier V. Inflammatory effect of intradermal administration of soluble phospholipase A2 in rabbits. J Invest Dermatol. 1986 Apr;86(4):380–383. doi: 10.1111/1523-1747.ep12285639. [DOI] [PubMed] [Google Scholar]
  44. Pruzanski W., Vadas P. Phospholipase A2--a mediator between proximal and distal effectors of inflammation. Immunol Today. 1991 May;12(5):143–146. doi: 10.1016/S0167-5699(05)80042-8. [DOI] [PubMed] [Google Scholar]
  45. Samuelsson B., Dahlén S. E., Lindgren J. A., Rouzer C. A., Serhan C. N. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987 Sep 4;237(4819):1171–1176. doi: 10.1126/science.2820055. [DOI] [PubMed] [Google Scholar]
  46. Schröder T., Kivilaakso E., Kinnunen P. K., Lempinen M. Serum phospholipase A2 in human acute pancreatitis. Scand J Gastroenterol. 1980;15(5):633–636. doi: 10.3109/00365528009182227. [DOI] [PubMed] [Google Scholar]
  47. Seilhamer J. J., Pruzanski W., Vadas P., Plant S., Miller J. A., Kloss J., Johnson L. K. Cloning and recombinant expression of phospholipase A2 present in rheumatoid arthritic synovial fluid. J Biol Chem. 1989 Apr 5;264(10):5335–5338. [PubMed] [Google Scholar]
  48. Sibilia M., Wagner E. F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science. 1995 Jul 14;269(5221):234–238. doi: 10.1126/science.7618085. [DOI] [PubMed] [Google Scholar]
  49. Smith J. B., Willis A. L. Aspirin selectively inhibits prostaglandin production in human platelets. Nat New Biol. 1971 Jun 23;231(25):235–237. doi: 10.1038/newbio231235a0. [DOI] [PubMed] [Google Scholar]
  50. Threadgill D. W., Dlugosz A. A., Hansen L. A., Tennenbaum T., Lichti U., Yee D., LaMantia C., Mourton T., Herrup K., Harris R. C. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science. 1995 Jul 14;269(5221):230–234. doi: 10.1126/science.7618084. [DOI] [PubMed] [Google Scholar]
  51. VAN DEENENL, DE HAAS G. H. THE SUBSTRATE SPECIFICITY OF PHOSPHOLIPASE A. Biochim Biophys Acta. 1963 Oct 22;70:538–553. doi: 10.1016/0006-3002(63)90792-3. [DOI] [PubMed] [Google Scholar]
  52. Vadas P. Elevated plasma phospholipase A2 levels: correlation with the hemodynamic and pulmonary changes in gram-negative septic shock. J Lab Clin Med. 1984 Dec;104(6):873–881. [PubMed] [Google Scholar]
  53. Vadas P., Pruzanski W., Kim J., Fornasier V. The proinflammatory effect of intra-articular injection of soluble human and venom phospholipase A2. Am J Pathol. 1989 Apr;134(4):807–811. [PMC free article] [PubMed] [Google Scholar]
  54. Vadas P., Pruzanski W. Role of secretory phospholipases A2 in the pathobiology of disease. Lab Invest. 1986 Oct;55(4):391–404. [PubMed] [Google Scholar]
  55. Vadas P., Pruzanski W., Stefanski E., Sternby B., Mustard R., Bohnen J., Fraser I., Farewell V., Bombardier C. Pathogenesis of hypotension in septic shock: correlation of circulating phospholipase A2 levels with circulatory collapse. Crit Care Med. 1988 Jan;16(1):1–7. doi: 10.1097/00003246-198801000-00001. [DOI] [PubMed] [Google Scholar]
  56. Vadas P., Stefanski E., Pruzanski W. Characterization of extracellular phospholipase A2 in rheumatoid synovial fluid. Life Sci. 1985 Feb 11;36(6):579–587. doi: 10.1016/0024-3205(85)90640-x. [DOI] [PubMed] [Google Scholar]
  57. Vane J. R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971 Jun 23;231(25):232–235. doi: 10.1038/newbio231232a0. [DOI] [PubMed] [Google Scholar]
  58. Vassar R., Fuchs E. Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation. Genes Dev. 1991 May;5(5):714–727. doi: 10.1101/gad.5.5.714. [DOI] [PubMed] [Google Scholar]
  59. Verger R., Ferrato F., Mansbach C. M., Pieroni G. Novel intestinal phospholipase A2: purification and some molecular characteristics. Biochemistry. 1982 Dec 21;21(26):6883–6889. doi: 10.1021/bi00269a040. [DOI] [PubMed] [Google Scholar]
  60. van den Bosch H. Intracellular phospholipases A. Biochim Biophys Acta. 1980 Sep 30;604(2):191–246. doi: 10.1016/0005-2736(80)90574-x. [DOI] [PubMed] [Google Scholar]
  61. van den Bosch H., van Deenen L. L. Chemical structure and biochemical significance of lysolecithins from rat liver. Biochim Biophys Acta. 1965 Oct 4;106(2):326–337. doi: 10.1016/0005-2760(65)90041-x. [DOI] [PubMed] [Google Scholar]

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