Takao Shimizu

Publications (187)1240.37 Total impact

• Source

  Available from: Makoto Murakami

  Dataset: ni.2586-S1

  Yoshitaka Taketomi, Noriko Ueno, Takumi Kojima, Hiroyasu Sato, Remi Murase, Kei Yamamoto, Satoshi Tanaka, Mariko Sakanaka, Masanori Nakamura, Yasumasa Nishito, [......], Yoshimichi Okayama, Chisei Ra, Kosuke Aritake, Yoshihiro Urade, Kazushi Morimoto, Yukihiko Sugimoto, Takao Shimizu, Shuh Narumiya, Shuntaro Hara, Makoto Murakami
• Article: Leukotriene B4 type-1 receptor signaling promotes liver repair after hepatic ischemia/reperfusion injury through the enhancement of macrophage recruitment.

  Hirotoki Ohkubo, Yoshiya Ito, Tsutomu Minamino, Toshiaki Mishima, Mitsuhiro Hirata, Kanako Hosono, Masabumi Shibuya, Takehiko Yokomizo, Takao Shimizu, Masahiko Watanabe, Masataka Majima
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  ABSTRACT: Recruited macrophages play a critical role in liver repair after acute liver injury. Leukotriene B4 (LTB4) is a potent chemoattractant for macrophages. In this study, we investigated the role of LTB4 receptor type 1 (BLT1) in liver repair during hepatic ischemia/reperfusion (I/R) injury. BLT1-knockout mice (BLT1(-/-)) or their wild-type counterparts (WT) were subjected to partial hepatic I/R. Compared with WT, BLT1(-/-) exhibited delayed liver repair and hepatocyte proliferation accompanied by a 70% reduction in the recruitment of macrophages and a 70-80% attenuation in hepatic expression of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1). Disruption of BLT1 signaling also reduced the expression of EGF by 67% on recruited macrophages expressing VEGFR1 in the injured liver. Treatment of WT mice with an EGF-neutralizing antibody delayed liver repair and reduced macrophage recruitment, compared with control immunoglobulin G (IgG). BLT1 signaling enhanced the expression of VEGF, VEGFR1, and EGF in isolated peritoneal macrophages in vitro. These results indicate that BLT1 signaling plays a role in liver repair after hepatic I/R through enhanced expression of EGF in recruited macrophages and that the development of a specific agonist for BLT1 could be useful for liver recovery from acute liver injury.-Ohkubo, H., Ito, Y., Minamino, T., Mishima, T., Hirata, M., Hosono, K., Shibuya, M., Yokomizo, T., Shimizu, T., Watanabe, M., Majima, M. Leukotriene B4 type-1 receptor signaling promotes liver repair after hepatic ischemia/reperfusion injury through the enhancement of macrophage recruitment.
  The FASEB Journal 04/2013; · 5.71 Impact Factor
• Source

  Available from: Makoto Murakami

  Article: Mast cell maturation is driven via a group III phospholipase A2-prostaglandin D2-DP1 receptor paracrine axis.

  Yoshitaka Taketomi, Noriko Ueno, Takumi Kojima, Hiroyasu Sato, Remi Murase, Kei Yamamoto, Satoshi Tanaka, Mariko Sakanaka, Masanori Nakamura, Yasumasa Nishito, [......], Yoshimichi Okayama, Chisei Ra, Kosuke Aritake, Yoshihiro Urade, Kazushi Morimoto, Yukihiko Sugimoto, Takao Shimizu, Shuh Narumiya, Shuntaro Hara, Makoto Murakami
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  ABSTRACT: Microenvironment-based alterations in phenotypes of mast cells influence the susceptibility to anaphylaxis, yet the mechanisms underlying proper maturation of mast cells toward an anaphylaxis-sensitive phenotype are incompletely understood. Here we report that PLA2G3, a mammalian homolog of anaphylactic bee venom phospholipase A2, regulates this process. PLA2G3 secreted from mast cells is coupled with fibroblastic lipocalin-type PGD2 synthase (L-PGDS) to provide PGD2, which facilitates mast-cell maturation via PGD2 receptor DP1. Mice lacking PLA2G3, L-PGDS or DP1, mast cell-deficient mice reconstituted with PLA2G3-null or DP1-null mast cells, or mast cells cultured with L-PGDS-ablated fibroblasts exhibited impaired maturation and anaphylaxis of mast cells. Thus, we describe a lipid-driven PLA2G3-L-PGDS-DP1 loop that drives mast cell maturation.
  Nature Immunology 04/2013; · 26.01 Impact Factor
• Article: Excitotoxicity-induced immediate surge in hippocampal prostanoid production has latent effects that promote chronic progressive neuronal death.

  Keisuke Yoshikawa, Yoshihiro Kita, Ayako Furukawa, Noriko Kawamura, Sanae Hasegawa-Ishii, Yoichi Chiba, Shiro Takei, Kei Maruyama, Takao Shimizu, Atsuyoshi Shimada
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  ABSTRACT: Excitotoxicity is involved in neurodegenerative conditions. We investigated the pathological significance of a surge in prostaglandin production immediately after kainic acid (KA) administration [initial phase], followed by a sustained moderate elevation in prostaglandin level [late phase] in the hippocampus of juvenile rats. Numerous pyknotic hippocampal neurons were observed 72h after KA treatment; this number remained elevated on days 10 and 30. Gross hippocampal atrophy was observed on days 10 and 30. Pre-treatment with indomethacin ameliorated neuronal death on days 10 and 30, and prevented hippocampal atrophy on day 30. Microglial response was moderated by the indomethacin pre-treatment. Blockade of only late-phase prostaglandin production by post-treatment with indomethacin ameliorated neuronal death on day 30. These findings suggest a role for initial-phase prostaglandin production in chronic progressive neuronal death, which is exacerbated by late-phase prostaglandin production. Blockade of prostaglandin production has therapeutic implications in preventing long-term neurological sequelae following excitotoxic brain damage.
  Prostaglandins Leukotrienes and Essential Fatty Acids 03/2013; · 3.37 Impact Factor
• Article: Arachidonoyl-phosphatidylcholine oscillates during the cell cycle and counteracts proliferation by suppressing Akt membrane binding.

  Andreas Koeberle, Hideo Shindou, Solveigh C Koeberle, Stefan A Laufer, Takao Shimizu, Oliver Werz
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  ABSTRACT: The activity of protein kinase B (Akt)-a major kinase promoting cell proliferation and survival-oscillates during the cell cycle. To investigate whether membrane phospholipids may regulate Akt phosphorylation and thus activity, we monitored the lipid profile of nocodazole-synchronized mouse NIH 3T3 fibroblasts during the cell cycle by liquid chromatography electrospray ionization tandem mass spectrometry (LC-MS/MS). The proportion of sn-2-arachidonoyl-phosphatidylcholine (20:4-PC) inversely correlated with Akt activity. Increasing the cellular ratio of 20:4-PC by supplementation of 20:4-PC to the cell culture medium diminished Akt [serine (Ser)473] phosphorylation. Saturated and monounsaturated phosphatidylcholines, used as control had no effect; 20:4-PC reduced cell proliferation relative to controls, interfered with S-phase transition, and suppressed Akt downstream signaling and cyclin expression like LY294002, which is a specific inhibitor of the phosphatidylinositol-3-kinase/Akt pathway. Additive effects of 20:4-PC and LY294002 were not observed, underlining the critical role of Akt for 20:4-PC signaling; 20:4-PC suppressed Akt membrane translocation as shown by immunofluorescence microscopy but left the concentration of the anchor lipid phosphatidylinositol-3,4,5-trisphosphate unchanged. An in vitro binding assay suggests that 20:4-PC attenuates the interaction of Akt with its membrane binding site. We conclude that 20:4-PC oscillates during the cell cycle and delays cell cycle progression by inhibiting Akt membrane binding.
  Proceedings of the National Academy of Sciences 01/2013; · 9.68 Impact Factor
• Article: Amino Acid residues of g-protein-coupled receptors critical for endoplasmic reticulum export and trafficking.

  Motonao Nakamura, Daisuke Yasuda, Nobuaki Hirota, Teruyasu Yamamoto, Satoshi Yamaguchi, Takao Shimizu, Teruyuki Nagamune
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  ABSTRACT: Analysis of the structural features of rhodopsin-type G-protein-coupled receptors (GPCRs) revealed the existence of an additional α-helix, termed helix 8, in the C-terminal tail. Furthermore, these GPCRs were determined to possess several conserved residues in their transmembrane domains. The functional deficiencies of receptors in which these domains or residues have been mutated have not been examined in living cells due to their accumulation in the endoplasmic reticulum (ER), although the ligand affinities of these receptors have been tested in membrane preparations. Recent studies have demonstrated that ER-accumulated receptors are effectively exported from ER using membrane permeable ligands as pharmacological chaperones. Here, we identified several residues of the platelet-activating factor receptor and leukotriene B(4) type-II receptor that are crucial for export from ER. Moreover, we used their specific ligands as pharmacological chaperones to traffic ER-accumulated GPCRs to the cell surface in order to examine the functional deficiencies of each mutant receptor. Here, we introduce the novel technique of site-specific N-terminal labeling of cell surface proteins in living cells with Sortase-A, a transpeptidase isolated from Staphylococcus aureus, to evaluate the trafficking of receptors after agonist stimulation.
  Methods in enzymology 01/2013; 521:203-16. · 1.90 Impact Factor
• Article: Decrease in circulating autotaxin by oral administration of prednisolone.

  Hayakazu Sumida, Kazuhiro Nakamura, Keisuke Yanagida, Ryunosuke Ohkawa, Yoshihide Asano, Takafumi Kadono, Kunihiko Tamaki, Koji Igarashi, Junken Aoki, Shinichi Sato, Satoshi Ishii, Takao Shimizu, Yutaka Yatomi
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  ABSTRACT: BACKGROUND: Autotaxin (ATX), secreted mainly from adipose tissue, functions as a lysophospholipase D (lysoPLD) to hydrolyze lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). ATX-LPA signaling is implicated in a wide range of physiological and pathophysiological processes including immune response. METHODS: The present study measured serum ATX antigen levels in patients with various autoimmune diseases using a recently developed automated enzyme immunoassay. In addition, serum lysoPLD activity was assessed by measuring choline liberation from the substrate LPC. Moreover, the effect of prednisolone (PSL) on mRNA expression of ATX was evaluated using cultured adipose tissue from mice. RESULTS: Decreased serum ATX antigen levels were observed after the initiation of treatment with PSL. The decreased levels recovered during tapering of PSL dose in a dose-dependent manner without exacerbation of disease activity. Moreover, decreased ATX mRNA expression in PSL-treated cultured murine adipose tissue suggested that the effect of PSL on serum ATX may have resulted from changes in adipose tissue ATX expression. CONCLUSIONS: Our results suggest that measurement of serum ATX antigen level may be clinically useful for the assessment of steroid treatment effect and drug compliance with steroids. Furthermore, our findings provide many novel insights into the biosynthesis, physiological functions, pathological roles, and clinical significance of circulating ATX.
  Clinica chimica acta; international journal of clinical chemistry 10/2012; · 2.54 Impact Factor
• Article: Current progress in non-Edg family LPA receptor research.

  Keisuke Yanagida, Yoshitaka Kurikawa, Takao Shimizu, Satoshi Ishii
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  ABSTRACT: Lysophosphatidic acid (LPA) is the simplest phospholipid yet possesses myriad biological functions. Until 2003, the functions of LPA were thought to be elicited exclusively by three subtypes of the endothelial differentiation gene (Edg) family of G protein-coupled receptors - LPA(1), LPA(2), and LPA(3). However, several biological functions of LPA could not be assigned to any of these receptors indicating the existence of one or more additional LPA receptor(s). More recently, the discovery of a second cluster of LPA receptors which includes LPA(4), LPA(5), and LPA(6) has paved the way for new avenues of LPA research. Analyses of these non-Edg family LPA receptors have begun to fill in gaps to understand biological functions of LPA such as platelet aggregation and vascular development that could not be ascribed to classical Edg family LPA receptors and are also unveiling new biological functions. Here we review recent progress in the non-Edg family LPA receptor research, with special emphasis on the pharmacology, signaling, and physiological roles of this family of receptors. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.
  Biochimica et Biophysica Acta 08/2012; · 4.66 Impact Factor
• Article: Palmitoleate is a mitogen, formed upon stimulation with growth factors, and converted to palmitoleoyl-phosphatidylinositol.

  Andreas Koeberle, Hideo Shindou, Takeshi Harayama, Takao Shimizu
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  ABSTRACT: Controversial correlations between biological activity and concentration of the novel lipokine palmitoleate (9Z-hexadecenoate, 16:1) might depend on the formation of an active 16:1 metabolite. For its identification, we analyzed the glycerophospholipid composition of mouse Swiss 3T3 fibroblasts in response to 16:1 using LC-MS/MS. 16:1 was either supplemented to the cell culture medium or endogenously formed when cells were stimulated with insulin or growth factors as suggested by the enhanced mRNA expression of 16:1-biosynthetic enzymes. The proportion of 1-acyl-2-16:1-sn-phosphatidylinositol (16:1-PI) was time-dependently and specifically increased relative to other glycerophospholipids under both conditions and correlated with the proliferation of fatty acid (16:1, palmitate, oleate, or arachidonate)-supplemented cells. Accordingly, cell proliferation was impaired by blocking 16:1 biosynthesis using the selective stearoyl-CoA desaturase-1 inhibitor CAY10566 and restored by supplementation of 16:1. The accumulation of 16:1-PI occurred throughout cellular compartments and within diverse mouse cell lines (Swiss 3T3, NIH-3T3, and 3T3-L1 cells). To elucidate further whether 16:1-PI is formed through the de novo or remodeling pathway of PI biosynthesis, phosphatidate levels and lyso-PI-acyltransferase activities were analyzed as respective markers. The proportion of 16:1-phosphatidate was significantly increased by insulin and growth factors, whereas lyso-PI-acyltransferases showed negligible activity for 16:1-coenzyme A. The relevance of the de novo pathway for 16:1-PI biosynthesis is supported further by the comparable incorporation rate of deuterium-labeled 16:1 and tritium-labeled inositol into PI for growth factor-stimulated cells. In conclusion, we identified 16:1 or 16:1-PI as mitogen whose biosynthesis is induced by growth factors.
  Journal of Biological Chemistry 06/2012; 287(32):27244-54. · 4.77 Impact Factor
• Article: Trehalose treatment suppresses inflammation, oxidative stress, and vasospasm induced by experimental subarachnoid hemorrhage.

  Ryosuke Echigo, Nobuyuki Shimohata, Kensuke Karatsu, Fumiko Yano, Yuko Kayasuga-Kariya, Ayano Fujisawa, Takayo Ohto, Yoshihiro Kita, Motonao Nakamura, Shigeki Suzuki, Manabu Mochizuki, Takao Shimizu, Ung-Il Chung, Nobuo Sasaki
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  ABSTRACT: Subarachnoid hemorrhage (SAH) frequently results in several complications, including cerebral vasospasm, associated with high mortality. Although cerebral vasospasm is a major cause of brain damages after SAH, other factors such as inflammatory responses and oxidative stress also contribute to high mortality after SAH. Trehalose is a non-reducing disaccharide in which two glucose units are linked by α,α-1,1-glycosidic bond, and has been shown to induce tolerance to a variety of stressors in numerous organisms. In the present study, we investigated the effect of trehalose on cerebral vasospasm, inflammatory responses, and oxidative stress induced by blood in vitro and in vivo. Enzyme immunoassay for eicosanoids, pro-inflammatory cytokines, and endothelin-1, and western blotting analysis for cyclooxygenase-2, inducible nitric oxide synthase, and inhibitor of NF-κB were examined in macrophage-like cells treated with hemolysate. After treatment with hemolysate and hydrogen peroxide, the levels of lipid peroxide and amounts of arachidonic acid release were also analyzed. Three hours after the onset of experimental SAH, 18 Japanese White rabbits received an injection of saline, trehalose, or maltose into the cisterna magna. Angiographic and histological analyses of the basilar arteries were performed. In a separate study, the femoral arteries from 60 rats were exposed to fresh autologous blood. At 1, 3, 5, 7, 10, and 20 days after treatment, cryosections prepared from the femoral arteries were histologically analyzed. When cells were treated with hemolysate, trehalose inhibited the production of several inflammatory mediators and degradation of the inhibitor of NF-κB and also suppressed the lipid peroxidation, the reactive oxygen species-induced arachidonic acid release in vitro. In the rabbit model, trehalose produced an inhibitory effect on vasospasm after the onset of experimental SAH, while maltose had only a moderate effect. When the rat femoral arteries exposed to blood were investigated for 20 days, histological analysis revealed that trehalose suppressed vasospasm, inflammatory response, and lipid peroxidation. These data suggest that trehalose has suppressive effects on several pathological events after SAH, including vasospasm, inflammatory responses, and lipid peroxidation. Trehalose may be a new therapeutic approach for treatment of complications after SAH.
  Journal of Translational Medicine 04/2012; 10:80. · 3.41 Impact Factor
• Article: A high-affinity monoclonal antibody against the FLAG tag useful for G-protein-coupled receptor study.

  Fumiyuki Sasaki, Toshiaki Okuno, Kazuko Saeki, Liu Min, Naoya Onohara, Haruyasu Kato, Takao Shimizu, Takehiko Yokomizo
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  ABSTRACT: The FLAG sequence (DYKDDDDK) is an artificial sequence widely used to detect, quantify, and purify proteins expressed as FLAG-fusion proteins. Several highly specific monoclonal antibodies for FLAG are commercially available; however, they are not always sensitive enough to detect proteins expressed at low levels and can give rise to unacceptable levels of background signal when used for immunostaining in vitro and in vivo. The current study reports the successful establishment of hybridoma cells that produce an extremely high-affinity antibody to FLAG, namely 2H8 Ab. 2H8 Ab stained FLAG-tagged G-protein-coupled receptors more strongly than commercially available antibodies in both flow cytometry and immunostaining experiments with no background staining. 2H8 was sensitive enough to detect FLAG-tagged G-protein-coupled receptors and soluble proteins in crude preparations, which could not be achieved using commercially available antibodies. Only 10 ng of 2H8 Ab was required to immunoprecipitate FLAG-tagged G-protein-coupled receptors from cell lysates. Of note, 2H8 stained FLAG-tagged BLT2, a low-affinity leukotriene B4 receptor, expressed in vivo in the small intestine of mice under control of the villin promoter. Thus, 2H8 Ab is a promising tool for analyzing various FLAG-fusion proteins, particularly G-protein-coupled receptors, both in vitro and in vivo.
  Analytical Biochemistry 03/2012; 425(2):157-65. · 3.00 Impact Factor
• Article: Correction to leukotriene receptors.

  Motonao Nakamura, Takao Shimizu
  Chemical Reviews 02/2012; 112(3):2012-3. · 40.20 Impact Factor
• Article: Lysophosphatidylcholine Acyltransferase 3 Is the Key Enzyme for Incorporating Arachidonic Acid into Glycerophospholipids during Adipocyte Differentiation.

  Miki Eto, Hideo Shindou, Andreas Koeberle, Takeshi Harayama, Keisuke Yanagida, Takao Shimizu
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  ABSTRACT: Cellular membranes contain glycerophospholipids, which have important structural and functional roles in cells. Glycerophospholipids are first formed in the de novo pathway (Kennedy pathway) and are matured in the remodeling pathway (Lands’ cycle). Recently, lysophospholipid acyltransferases functioning in Lands’ cycle were identified and characterized. Several enzymes involved in glycerophospholipid biosynthesis have been reported to have important roles in adipocytes. However, the role of Lands’ cycle in adipogenesis has not yet been reported. Using C3H10T1/2, a cell line capable of differentiating to adipocyte-like cells in vitro, changes of lysophospholipid acyltransferase activities were investigated. Lysophosphatidylcholine acyltransferase (LPCAT), lysophosphatidylethanolamine acyltransferase (LPEAT) and lysophosphatidylserine acyltransferase (LPSAT) activities were enhanced, especially with 18:2-CoA and 20:4-CoA as donors. Correspondingly, mRNA expression of LPCAT3, which possesses LPCAT, LPEAT and LPSAT activities with high specificity for 18:2- and 20:4-CoA, was upregulated during adipogenesis. Analysis of acyl-chain compositions of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS) showed a change in their profiles between preadipocytes and adipocytes, including an increase in the percentage of arachidonic acid-containing phospholipids. These changes are consistent with the activities of LPCAT3. Therefore, it is possible that enhanced phospholipid remodeling by LPCAT3 may be associated with adipocyte differentiation.
  International Journal of Molecular Sciences 01/2012; 13(12):16267-80. · 2.60 Impact Factor
• Article: Human FcγRIIA induces anaphylactic and allergic reactions.

  Friederike Jönsson, David A Mancardi, Wei Zhao, Yoshihiro Kita, Bruno Iannascoli, Huot Khun, Nico van Rooijen, Takao Shimizu, Lawrence B Schwartz, Marc Daëron, Pierre Bruhns
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  ABSTRACT: IgE and IgE receptors (FcεRI) are well-known inducers of allergy. We recently found in mice that active systemic anaphylaxis depends on IgG and IgG receptors (FcγRIIIA and FcγRIV) expressed by neutrophils, rather than on IgE and FcεRI expressed by mast cells and basophils. In humans, neutrophils, mast cells, basophils, and eosinophils do not express FcγRIIIA or FcγRIV, but FcγRIIA. We therefore investigated the possible role of FcγRIIA in allergy by generating novel FcγRIIA-transgenic mice, in which various models of allergic reactions induced by IgG could be studied. In mice, FcγRIIA was sufficient to trigger active and passive anaphylaxis, and airway inflammation in vivo. Blocking FcγRIIA in vivo abolished these reactions. We identified mast cells to be responsible for FcγRIIA-dependent passive cutaneous anaphylaxis, and monocytes/macrophages and neutrophils to be responsible for FcγRIIA-dependent passive systemic anaphylaxis. Supporting these findings, human mast cells, monocytes and neutrophils produced anaphylactogenic mediators after FcγRIIA engagement. IgG and FcγRIIA may therefore contribute to allergic and anaphylactic reactions in humans.
  Blood 12/2011; 119(11):2533-44. · 9.90 Impact Factor
• Article: Analysis of Two Major Intracellular Phospholipases A2 (PLA2) in Mast Cells Reveals Crucial Contribution of Cytosolic PLA2α, Not Ca2+-independent PLA2β, to Lipid Mobilization in Proximal Mast Cells and Distal Fibroblasts

  Noriko Ueno, Yoshitaka Taketomi, Kei Yamamoto, Tetsuya Hirabayashi, Daisuke Kamei, Yoshihiro Kita, Takao Shimizu, Koei Shinzawa, Yoshihide Tsujimoto, Kazutaka Ikeda, Ryo Taguchi, Makoto Murakami
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  ABSTRACT: Mast cells release a variety of mediators, including arachidonic acid (AA) metabolites, to regulate allergy, inflammation, and host defense, and their differentiation and maturation within extravascular microenvironments depend on the stromal cytokine stem cell factor. Mouse mast cells express two major intracellular phospholipases A2 (PLA2s), namely group IVA cytosolic PLA2 (cPLA2α) and group VIA Ca2+-independent PLA2 (iPLA2β), and the role of cPLA2α in eicosanoid synthesis by mast cells has been well documented. Lipidomic analyses of mouse bone marrow-derived mast cells (BMMCs) lacking cPLA2α (Pla2g4a−/−) or iPLA2β (Pla2g6−/−) revealed that phospholipids with AA were selectively hydrolyzed by cPLA2α, not by iPLA2β, during FcϵRI-mediated activation and even during fibroblast-dependent maturation. Neither FcϵRI-dependent effector functions nor maturation-driven phospholipid remodeling was impaired in Pla2g6−/− BMMCs. Although BMMCs did not produce prostaglandin E2 (PGE2), the AA released by cPLA2α from BMMCs during maturation was converted to PGE2 by microsomal PGE synthase-1 (mPGES-1) in cocultured fibroblasts, and accordingly, Pla2g4a−/− BMMCs promoted microenvironmental PGE2 synthesis less efficiently than wild-type BMMCs both in vitro and in vivo. Mice deficient in mPGES-1 (Ptges−/−) had an augmented local anaphylactic response. These results suggest that cPLA2α in mast cells is functionally coupled, through the AA transfer mechanism, with stromal mPGES-1 to provide anti-anaphylactic PGE2. Although iPLA2β is partially responsible for PGE2 production by macrophages and dendritic cells, it is dispensable for mast cell maturation and function.
  Journal of Biological Chemistry 10/2011; 286(43):37249-37263. · 4.77 Impact Factor
• Article: Polyunsaturated fatty acids are incorporated into maturating male mouse germ cells by lysophosphatidic acid acyltransferase 3.

  Andreas Koeberle, Hideo Shindou, Takeshi Harayama, Koichi Yuki, Takao Shimizu
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  ABSTRACT: Long-chain polyunsaturated fatty acids (PUFAs) accumulate in mammalian testis during puberty and are essential for fertility. To investigate whether lysophospholipid acyltransferases determine the PUFA composition of testicular phospholipids during pubertal development, we compared their mRNA expression, in vitro activity, and specificity with the lipidomic profile of major phospholipids. The accumulation of PUFAs in phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine correlated with an induced lysophosphatidic acid acyltransferase (LPAAT)3 mRNA expression, increased microsomal LPAAT3 activity, and shift of LPAAT specificity to PUFA-coenzyme A. LPAAT3 was induced during germ cell maturation, as shown by immunofluorescence microscopy. Accordingly, differentiation of mouse GC-2spd(ts) spermatocytes into spermatides up-regulated LPAAT3 mRNA, increased the amount of polyunsaturated phospholipids, and shifted the specificity for the incorporation of deuterium-labeled docosahexaenoic acid toward phosphatidylcholine and phosphatidylethanolamine. Stable knockdown of LPAAT3 in GC-2spd(ts) cells significantly decreased microsomal LPAAT3 activity, reduced levels of polyunsaturated phosphatidylethanolamine species, and impaired cell proliferation/survival during geneticin selection. We conclude that the induction of LPAAT3 during germ cell development critically contributes to the accumulation of PUFAs in testicular phospholipids, thereby possibly affecting sperm cell production.
  The FASEB Journal 10/2011; 26(1):169-80. · 5.71 Impact Factor
• Article: International Union of Basic and Clinical Pharmacology. LXXXIV: leukotriene receptor nomenclature, distribution, and pathophysiological functions.

  Magnus Bäck, Sven-Erik Dahlén, Jeffrey M Drazen, Jilly F Evans, Charles N Serhan, Takao Shimizu, Takehiko Yokomizo, G Enrico Rovati
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  ABSTRACT: The seven-transmembrane G protein-coupled receptors activated by leukotrienes are divided into two subclasses based on their ligand specificity for either leukotriene B(4) or the cysteinyl leukotrienes (LTC(4), LTD(4), and LTE(4)). These receptors have been designated BLT and CysLT receptors, respectively, and a subdivision into BLT(1) and BLT(2) receptors and CysLT(1) and CysLT(2) receptors has been established. However, recent findings have also indicated the existence of putative additional leukotriene receptor subtypes. Furthermore, other ligands interact with the leukotriene receptors. Finally, leukotrienes may also activate other receptor classes, such as purinergic receptors. The aim of this review is to provide an update on the pharmacology, expression patterns, and pathophysiological roles of the leukotriene receptors as well as the therapeutic developments in this area of research.
  Pharmacological reviews 09/2011; 63(3):539-84. · 17.00 Impact Factor
• Article: Analysis of two major intracellular phospholipases A(2) (PLA(2)) in mast cells reveals crucial contribution of cytosolic PLA(2)α, not Ca(2+)-independent PLA(2)β, to lipid mobilization in proximal mast cells and distal fibroblasts.

  Noriko Ueno, Yoshitaka Taketomi, Kei Yamamoto, Tetsuya Hirabayashi, Daisuke Kamei, Yoshihiro Kita, Takao Shimizu, Koei Shinzawa, Yoshihide Tsujimoto, Kazutaka Ikeda, Ryo Taguchi, Makoto Murakami
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  ABSTRACT: Mast cells release a variety of mediators, including arachidonic acid (AA) metabolites, to regulate allergy, inflammation, and host defense, and their differentiation and maturation within extravascular microenvironments depend on the stromal cytokine stem cell factor. Mouse mast cells express two major intracellular phospholipases A(2) (PLA(2)s), namely group IVA cytosolic PLA(2) (cPLA(2)α) and group VIA Ca(2+)-independent PLA(2) (iPLA(2)β), and the role of cPLA(2)α in eicosanoid synthesis by mast cells has been well documented. Lipidomic analyses of mouse bone marrow-derived mast cells (BMMCs) lacking cPLA(2)α (Pla2g4a(-/-)) or iPLA(2)β (Pla2g6(-/-)) revealed that phospholipids with AA were selectively hydrolyzed by cPLA(2)α, not by iPLA(2)β, during FcεRI-mediated activation and even during fibroblast-dependent maturation. Neither FcεRI-dependent effector functions nor maturation-driven phospholipid remodeling was impaired in Pla2g6(-/-) BMMCs. Although BMMCs did not produce prostaglandin E(2) (PGE(2)), the AA released by cPLA(2)α from BMMCs during maturation was converted to PGE(2) by microsomal PGE synthase-1 (mPGES-1) in cocultured fibroblasts, and accordingly, Pla2g4a(-/-) BMMCs promoted microenvironmental PGE(2) synthesis less efficiently than wild-type BMMCs both in vitro and in vivo. Mice deficient in mPGES-1 (Ptges(-/-)) had an augmented local anaphylactic response. These results suggest that cPLA(2)α in mast cells is functionally coupled, through the AA transfer mechanism, with stromal mPGES-1 to provide anti-anaphylactic PGE(2). Although iPLA(2)β is partially responsible for PGE(2) production by macrophages and dendritic cells, it is dispensable for mast cell maturation and function.
  Journal of Biological Chemistry 08/2011; 286(43):37249-63. · 4.77 Impact Factor
• Article: Leukotriene receptors.

  Motonao Nakamura, Takao Shimizu
  Chemical Reviews 04/2011; 111(10):6231-98. · 40.20 Impact Factor
• Source

  Available from: pnas.org

  Article: Prostaglandin E2-prostaglandin E receptor subtype 4 (EP4) signaling mediates UV irradiation-induced systemic immunosuppression.

  Kitipong Soontrapa, Tetsuya Honda, Daiji Sakata, Chengcan Yao, Takako Hirata, Shohei Hori, Toshiyuki Matsuoka, Yoshihiro Kita, Takao Shimizu, Kenji Kabashima, Shuh Narumiya
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  ABSTRACT: UV radiation induces systemic immunosuppression. Because nonsteroidal anti-inflammatory drugs suppress UV-induced immunosuppression, prostanoids have been suspected as a crucial mediator of this UV effect. However, the identity of the prostanoid involved and its mechanism of action remain unclear. Here, we addressed this issue by subjecting mice deficient in each prostanoid receptor individually or mice treated with a subtype-specific antagonist to UV irradiation. Mice treated with an antagonist for prostaglandin E receptor subtype 4 (EP4), but not those deficient in other prostanoid receptors, show impaired UV-induced immunosuppression, whereas administration of an EP4 agonist rescues the impairment of the UV-induced immunosuppression in indomethacin-treated mice. The EP4 antagonist treatment suppresses an increase in the number of CD4(+)/forkhead box P3-positive (Foxp3(+)) regulatory T cells (Treg cells) in the peripheral lymph nodes (LNs) and dendritic cells expressing DEC205 in the LNs and the skin after UV irradiation. Furthermore, the EP4 antagonist treatment down-regulates UV-induced expression of receptor activator of NF-κB ligand (RANKL) in skin keratinocytes. Finally, administration of anti-RANKL antibody abolishes the restoration of UV-induced immunosuppression by EP4 agonism in indomethacin-treated mice. Thus, prostaglandin E(2) (PGE(2))-EP4 signaling mediates UV-induced immunosuppression by elevating the number of Treg cells through regulation of RANKL expression in the epidermis.
  Proceedings of the National Academy of Sciences 04/2011; 108(16):6668-73. · 9.68 Impact Factor