Analyses of phospholipase A_2 enzymes that are involved in signaling and non-signaling events

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 14207098
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Showa University
• Principal Investigator: KUDO Ichiro Showa University, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (30134612)
• Co-Investigator(Kenkyū-buntansha): NAKATANI Yoshihito Showa University, School of Pharmaceutical Sciences, Assistant, 薬学部, 講師 (80266163) ; SHIMABARA Satoko Showa University, School of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (60266161) ; KUWATA Hiroshi Showa University, School of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (80286864)
• Project Period (FY): 2002 – 2005
• Keywords: phospholipase A2 / phospholipid / arachidonate metabolism / knockout mice / transgenic mice / lipoprotein / metabolic syndrome / inflammation

Research Abstract

More than 20 phospholipase A_2 (PLA_2) enzymes, which hydrolyze the sn-2 position of glycerophospholipids to liberate fatty acids and lysophospholipids, have been identified in mammals. This study aims to clarify the functions of individual PLA_2 enzymes. In this year, we examined the functions of two secretory PLA_2 (sPLA_2) isozymes in vivo using their transgenic (Tg) and knockout (KO) mice.
On the basis of our recent finding that group X sPLA_2 (sPLA_2-X) is located in peripheral neuronal fibers, we herein looked for some neuronal phenotypes in sPLA_2-X KO mice. We found that the pain nociception induced by intraperitoneal administration of acetic acid was significantly reduced in sPLA_2-X KO mice as compared with that in replicate wild-type (WT) mice. Conversely, enhanced pain response was observed in sPLA_2-X Tg mice relative to that in WT mice. Immunohistochemistry revealed that the immunoreactive sPLA_2-X staining was found in the sciatic nerve fibers as well as in dorsal root ga nglions adjacent to the spinal cord. We therefore speculate that the neuron-associated sPLA_2-X may play a regulatory role in the neuronal transmission through as yet unknown mechanisms.
We found that group III sPLA_2 (sPLA_2-III) Tg mice displayed altered plasma lipoprotein composition manifested by decreased HDL and increased modified LDL levels, an event that is generally believed to be linked to atherosclerosis. The view that sPLA_2-III might be involved in the process of atherosclerosis was further supported by immunohistochemical observation that sPLA_2-III immunoreactivity was found in the atherosclerotic lesions in humans as well as those in apoE-deficicent mice. Moreover, sPLA_2-III Tg mice fed with high-fat diet exhibited obesity relative to replicate WT mice. In addition to these metabolic syndrome-like phenotypes, passive cutaneous anaphylactic reaction was elevated in sPLA_2-III Tg mice relative to replicate WT mice, and splenomegaly and dermatitis occurred spontaneously and progressively in aged sPLA_2-III Tg mice, suggesting unexplored actions of sPLA_2-III on the immune system. Finally, we have succeeded in generating sPLA_2-III-deficient mice, which will unveil the physiological relevance of the aforementioned pathogenic aspects observed in sPLA_2-III Tg mice.

Research Products

• [Journal Article] Group V and X secretory phospholipase A_2s prevent adenovirus infection into mammalian cells. (2006)
  • Author(s): Mitsuishi, M., Masuda, S., Kudo, I., Murakami, M.
  • Journal Title: Biochem J. 393 Pages: 97-106
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Searcu of factors that inermediate cytokine-indeced IIA Phospholipase A_2 expression through the cytosolic phospholipase A_2-and 12/(15)-lipoxygenase-dependent pathway (2005)
  • Author(s): Kuwata, H., Nonaka, T., Murakami, M, Kudo, I
  • Journal Title: J. Biol. Chem. 280 Pages: 15830-25839
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cellular distribution, post-translational modification, and tumorigenic potential of human group III secreted phospholipase A_2 (2005)
  • Author(s): Murakami, M., Masuda, S., Shimbara, S., Isikawa, Y., Ishii, T., Kudo, I
  • Journal Title: J. Biol. Chem. 280 Pages: 24987-24998
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Neuronal expression and neuritogenic action of group X secreted phospholipase A_2 (2005)
  • Author(s): Masuda, S., Murakami, M., Takanezawa, Y., Aoki, J., Arai, H., Ishikawa, Y., Ishii, T., et al.
  • Journal Title: J. Biol. Chem. 280 Pages: 23203-23214
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Group VIB Ca^<2+>-independent phospholipase A_2 (iPLA_2γ) promotes cellular membrane hydrolysis and prostaglandin production in a manner distinct from other intracellular phospholipase A_2S (2005)
  • Author(s): Murakami, M, Masuda, S., Ueda-Semmyo, K., Yoda, E., Kuwata, H., Takanezawa, Y., Aoki, J, et al.
  • Journal Title: J. Biol. Chem. 280 Pages: 14028-14041
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of secretory phospholipase A_2 enzymes in lungs of humans with pneumonia and their potential prostaglandin-synthetic function in human lung-derived cells (2005)
  • Author(s): Masuda, S., Murakami, M., Mitsuishi, M., Komiyama, K., Ishikawa, Y., Ishii, T., Kudo, I.
  • Journal Title: Biochem. J. 387 Pages: 27-38
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Various secretory phospholipase A_2 enzymes are expressed in rheumatoid arthritis and augment prostaglandin production in cultured synovial cells (2005)
  • Author(s): Masuda, S., Murakami, M., Komiyama, K., Ishihara, M., Ishikawa, Y., Ishii, T., Kudo, I.
  • Journal Title: FEBS J. 272 Pages: 655-672
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Diverse cellular localizations of secretory phospholipase A_2 enzymes in several human tissues. (2005)
  • Author(s): Masuda, S., Murakami, M., Ishikawa, Y., Ishii, T., Kudo, I.
  • Journal Title: Biochim.Biophys.Acta 1736 Pages: 200-210
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Search of factors that intermediate cytokine-induced group IIA phospholipase A_2 expression through the cytosolic phospholipase A_2- and 12/15-lipoxygenase-dependent pathway. (2005)
  • Author(s): Kuwata, H., Nonaka, T., Murakami, M., Kudo, I.
  • Journal Title: J.Biol.Chem. 280 Pages: 25830-25839
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cellular distribution, post-translational modification, and tumorigenic potential of human group III secreted phospholipase A_2. (2005)
  • Author(s): Murakami, M., Masuda, S., Shimabara, S., Ishikawa, Y., Ishii, T., Kudo, I.
  • Journal Title: J.Biol.Chem. 280 Pages: 24987-24998
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neuronal expression and neuritogenic action of group X secreted phospholipase A_2. (2005)
  • Author(s): Masuda, S., Murakami, M., Takanezawa, Y., Aoki, J., Arai, H., Ishikawa, Y., Ishii, T., Arioka, M., Kudo, I.
  • Journal Title: J.Biol.Chem. 280 Pages: 23203-23214
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Group VIB Ca^<2+>-independent phospholipase A_2 (iPLA_γ) promotes cellular membrane hydrolysis and prostaglandin production in a manner distinct from other intracellular phospholipase A_2s. (2005)
  • Author(s): Murakami, M., Masuda, S., Ueda-Semmyo, K., Yoda, E., Kuwata, H., Takanezawa, Y., Aoki, J., Arai, H., Sumimoto, H., Ishikawa, Y., Ishii, T., Nakatani, Y., Kudo, I.
  • Journal Title: J.Biol.Chem. 280 Pages: 14028-14041
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of secretory phospholipase A_2 enzymes in lungs of humans with pneumonia and their potential prostaglandin-synthetic function in human lung-derived cells. (2005)
  • Author(s): Masuda, S., Murakami, M., Mitsuishi, M., Komiyama, K., Ishikawa, Y., Ishii, T., Kudo, I.
  • Journal Title: Biochem.J. 387 Pages: 27-38
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of type V secretory phospholipase A_2 in myocardial remodeling after infarction. (2005)
  • Author(s): Ishikawa, Y., Komiyama, I., Masuda, S., Murakami, M., Akasaka, Y., Ito, K., Akishima, Y., Kimura, M., Fujimoto, A., Kudo, I., Ishii, T.
  • Journal Title: Histopathology 47 Pages: 257-267
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Various secretory phospholipase A_2 enzymes are expressed in rheumatoid arthritis and augment prostaglandin production in cultured synovial cells. (2005)
  • Author(s): Masuda, S., Murakami, M., Komiyama, K., Ishihara, M., Ishikawa, Y., Ishii, T., Kudo, I.
  • Journal Title: FEBS J. 272 Pages: 655-672
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] ホスホリパーゼA_2研究の展開 (2005)
  • Author(s): 村上 誠, 工藤 一郎
  • Journal Title: 実験医学 23, No.6 Pages: 878-885
  • Description: 「研究成果報告書概要(欧文)」より
• [Patent(Industrial Property Rights)] Group III secretory phospholipase A_2(sPLA_2-III) for therapy and diagnosis (2005)
  • Inventor(s): Kudo, I, Murakami, M, Tsutsumi, K., Hatakeyama, S.
  • Industrial Property Rights Holder: Novartis Pharma
  • Industrial Property Number: 特許 PC4-34577P1
  • Filing Date: 2005-10-19
  • Description: 「研究成果報告書概要(和文)」より