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Role of Sphingosine 1-Phosphate Receptor Type 1 in Lymphocyte Egress from Secondary Lymphoid Tissues and Thymus

Cellular & Molecular Immunology 2006年第1期3卷 11-19页

作者： Kenji Chiba Hirofumi Matsuyuki Yasuhiro Maeda kunio sugahara Research Laboratory Ⅲ (Immunology) Pharmaceutical Research UnitResearch and Development DivisionMitsubishi Pharma CorporationYokohamaJapan

Circulation of mature lymphocytes between blood and secondary lymphoid tissues plays a central role in the immune system. Homing of lymphocytes from blood into secondary lymphoid tissues beyond high endothelial venules is highly dependent on the interaction between the chemokines CCL19, CCL21, CXCL12, and CXCL13, and their receptors CCR7, CXCR4 and CXCR5. However, the molecular mechanism（s） of lymphocyte egress from secondary lymphoid tissues to lymph remained unclear. We have found a new class of immunomodulator, FTY720 by chemical modification of vegetative wasp-derived natural product, ISP-I （myriocin）. FTY720 has been shown to be highly effective in experimental allograft and autoimmune disease models. A striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunomodulating activity in these models. The reduction of circulating lymphocytes by FTY720 is caused by sequestration of lymphocytes into secondary lymphoid tissues and thymus. FTY720 is rapidly converted to （S）-enantiomer of FTY720-phosphate [（S）-FTY720-P] by sphingosine kinase 2 in vivo. （S）-FTY720-P acting as a potent agonist of S1P receptor type 1 （S1P1）, induces long-term down-regulation of S1P1 on lymphocytes, and thereby inhibits the migration of lymphocytes toward S1P. Thus, it is presumed that FTY720-induced lymphocyte sequestration is due to the inhibition of S1P/S1P1-dependent lymphocyte egress from secondary lymphoid tissues and thymus by its active metabolite （S）-FTY720-P. Throughout the analysis of the mechanism of action of FTY720, it is clarified that S1P/S1P1 interaction plays an important role for lymphocyte egress from secondary lymphoid tissues and thymus.

关键词： FTY720 SIP S1P1 immunomodulation lymphocyte egress

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Involvement of Sphingosine 1-Phosphate (S1P) Receptor Type 1 and Type 4 in Migratory Response of Mouse T Cells toward S1P

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Cellular & Molecular Immunology 2006年第6期3卷 429-437页

作者： Hirofumi Matsuyuki Yasuhiro Maeda Kazuhiro Yano kunio sugahara Kenji Chiba Takayuki Kohno Yasuyuki Igarashi Research Laboratory III (Immunology) Pharmaceuticals Research Division Mitsubishi Pharma Corporation Yokohama Japan Discovery Technology Laboratory Pharmaceuticals Research Division Mitsubishi Pharma Corporation Yokohama Japan Department of Biomembrane and Biofunctional Chemistry Graduate School of Pharmaceutical Sciences Hokkaido University Sapporo Japan

Sphingosine 1-phosphate （S1P）, a pleiotropic lysophospholipid, regulates signal transduction pathway via Gprotein-coupled receptors termed S1P1-5 in several types of the cells including lymphocytes. Higher levels of S1P4 mRNA as well as S1P1 mRNA are expressed in lymphoid tissues such as the spleen, thymus, lymph nodes, and Payer＇s patches. In contrast to S1P1 that plays an essential role in lymphocyte egress, little is known about the role of S1P4 in immune system. In this study, we found that S1P at 10 to 100 nM significantly induced the cell migration and the significant levels of S1P1 and S1P4 mRNA were expressed in mouse CD4 T cells, D10.G4.1 mouse Th2 cells, and ***-2 mouse thymoma cells. In D10.G4.1 and ***-2 cells, S1P-induced migration was almost completely inhibited by pretreatment with pertussis toxin, Clostoridium difficile toxin B, and （S）-enantiomer of FTY720-phosphate, a potent agonist at S1P1 and S1P4. The members of the Rho family small GTPase, Cdc42 and Rac were activated by S1P stimulation in these cells. The transfection with dominant negative or constitutively active forms of Cdc42 and Rac revealed that the activation of both Cdc42 and Rac is essential for S1P-induced migration of these cells. The immunoprecipitation assays using CHO cells co-expressing both S1P4 and S1P1 receptors indicated that S1P4 and S1P1 are associated on the cell surface. These results suggest that the association of S1P4 and S1PI plays an important role in migratory response of mouse T cells toward S1P.

关键词： S1Pi S1P4 S1P FTY720 T cell migration

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Role of Sphingosine 1-Phosphate (S1P) Receptor 1 in Experimental Autoimmune Encephalomyelitis —II

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Pharmacology & Pharmacy 2013年第8期4卷 638-646页

作者： Noriyasu Seki Hirotoshi Kataoka kunio sugahara Atsushi Fukunari Kenji Chiba Advanced Medical Research Laboratories Research Division Mitsubishi Tanabe Pharma Corporation Yokohama Japan. Pharmacology Research Laboratories I Research Division Mitsubishi Tanabe Pharma Corporation Yokohama Japan Pharmacology Research Laboratories I Research Division Mitsubishi Tanabe Pharma Corporation Yokohama Japan Pharmacology Research Laboratories I Research Division Mitsubishi Tanabe Pharma Corporation Yokohama Japan Advanced Medical Research Laboratories Research Division Mitsubishi Tanabe Pharma Corporation Yokohama Japan.

Therapeutic administration of fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine 1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. However, this treatment showed an only partial inhibition of Th1/Th17 cell infiltration into the central nervous system (CNS), suggesting that down-regulation of lymphocytic S1P1 is insufficient to explain the therapeutic effect of FTY720 on EAE. On the other hand, the therapeutic administration of FTY720 reduced the mRNA expressions of IL-6, CCL2, and glial fibrillary acidic protein, an activation marker of astrocytes, in the CNS of EAE mice. In human astrocytic glyoma, U373MG cells, mRNA expression of S1P1 was higher as compared with those of the other S1P receptor subtypes and phosphorylation of Akt was induced by S1P, FTY720-phosphate (FTY720-P), or an S1P1-selective agonist, SEW2871. FTY720-P appeared to induce down-regulation of S1P1 in U373MG cells, implying a functional antagonism at S1P1 on astrocytes. S1P but not FTY720-P induced production of IL-6, IL-8, and CCL2 significantly and treatment with FTY720-P or SEW2871 inhibited production of these pro-inflammatory cytokines from U373MG cells stimulated with S1P. These results suggest that S1P-S1P1 axis induces production of pro-inflammatory cytokines by astrocytes. Consequently, it is highly probable that the therapeutic effects of FTY720 on EAE are caused by inhibiting not only egress of myelin-specific Th cells from the draining lymph nodes but also activation of astrocytes in the CNS.

关键词： Sphingosine 1-Phosphosphate Receptor 1 Fingolimod Hydrochloride (FTY720) Experimental Autoimmune Encephalomyelitis Astrocytes Pro-Inflammatory Cytokines

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Type-dependent differential expression of neuropeptide Y in chicken hypothalamus (Gallus domesticus)

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2007年第11期8卷 839-844页

作者： CHEN Gui-qian HU Xiu-fang sugahara kunio CHEN Ji-shuang SONG Xue-mei ZHENG Hui-chao JIANG Yong-qing HUANG Xin JIANG Jun-fang ZHOU Wei-dong Institute of Bioengineering Zhejiang Sci- Tech University Hangzhou 310018 China Institute of Animal Husbandry and Veterinary Science Zhejiang Academy of Agricultural Sciences Hangzhou 310021 China Laboratory of Nutritional Biochemistry Department of Animal Science Faculty of Agriculture Utsunomiya University Utsunomiya 321-8505 Japan

Neuropeptide Y （NPY） is one of the most important orexigenic agents in central regulation of feeding behavior, body weight and energy homeostasis in domestic chickens. To examine differences in the hypothalamic NPY between layer-type and meat-type of chickens, which are two divergent kinds of the domestic chickens in feeding behavior and body weight, we detected mRNA levels of NPY in hypothalamic infundibular nucleus （IN）, paraventricular nucleus （PVN） and lateral hypothalamic area （LHA） of these two types of chickens using one-step real time RT-PCR. The meat-type chicken had more food daily （about 1.7 folds） and greater body weights （about 1.5 folds） and brain weights than the layer-type chicken at the age of 14 d. In the meat-type of chicken, NPY mRNA levels of the IN and PVN were significantly greater than those of the LHA, and were not significantly different between the lN and PVN. However, in the layer-type of chicken, NPY mRNA levels were significantly greater in the IN than those in the LHA and PVN, and were not significantly different between the PVN and LHA. In all these hypothalamic regions the layer-type of chicken had significantly higher NPY mRNA levels than the meat-type chicken did. These results suggest the expression of NPY in the hypothalamus has a type-dependent pattern in domestic chickens.

关键词： Neuropeptide Y (NPY) Hypothalamus Message RNA (mRNA) Meat-type chicken Layer-type chicken

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