Identification of cytokines secreted by Niemann-Pick cells

• Project/Area Number: 14570077
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Tottori University
• Principal Investigator: NINOMIYA Haruaki Tottori University, Department of Neurobiology, Associate Professor, 医学部, 助教授 (80212124)
• Project Period (FY): 2002 – 2003
• Project Status: Completed (Fiscal Year 2003)
• Budget Amount: ¥3,000,000 (Direct Cost: ¥3,000,000); Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
• Keywords: Niemann-Pick / cytokine / cholesterol / サイトカイン / ニーマンピック病 / NPC1 / IL-6

Research Abstract

cDNA microarray analyses revealed increased mRNA levels of interferon-stimulated response element (ISRE)-driven genes such as MxA (myxovirus resistance A) and 2'-5' oligoadenylate synthetase in Niemann-pick disease type C (NPC) human skin fibroblasts. Of the proteins located upstream to ISRE, levels of STArs (signal transducers and activators of transcription) were increased in these cells. Similar increases in STAT levels were detected in extracts from NPC1-deficient CHO cells and NPC mouse brain and liver. In NPC mouse brain sections, reactive glial cells contained high STAT-3 immunoreactivity. Conditioned media from NPC fibroblasts contained high levels of proinflammatory cytokines interferon-β, IL-6, IL-8 and had activities to induce luciferase expression driven by ISRE, STAT-3 as well as GAS, and also to induce MxA expression in control cells. The activities to induce expression of ISRE-driven luciferase and MxA were absorbed by a neutralizing antibody against interferon-β whereas activities to induce expression of STAT-3-or GAS-driven luciferase were absorbed by a neutralizing antibody against IL-6. These results suggest constitutive activation of STAT signaling due to proinflammatory cytokines both in cultured NPC cells and mouse tissues.

Research Products

• [Publications] Kato Y. 他: "^1H, ^<13>C and ^<15>N assignments of the tandem WW domains of human MAGI-1/BAP-1."J.Biomol.NMR. (印刷中). (2004)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ohsaki Y. 他: "Reduced sensitivity of Niemann-Pick C1-deficient cells to θ-toxin (perfringolysin O) : sequestration of toxin to raft-enriched membrane vesicles."Histochem. Cell Biol.. (印刷中). (2004)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Wakutani Y. 他: "Novel amyloid precursor protein gene missense mutation (D678N) in familial Alzheimer's disease."J.Neurol.Neurosurg.Psychiat.. (印刷中). (2004)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Feng J.H. 他: "Novel TSC2 mutations and decreased expression of tuberin in cultured tumor cells with an insertion mutation."Hum.Mutat.. 24. 397 (2004)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Matsuzawa F. 他: "Structural basis of GM2 gangliosidosis B variant."J.Hum.Genet.. 48. 582-589 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sugii S. 他: "Biotinylated theta-toxin derivative as a probe to examine intracellular cholesterol-rich domains in normal and Niemana-Pick type C1 cells."J. Lipid Res.. 44. 1033-1041 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Hou L., Sugimoto Y., Ohsaki Y., Ninomiya H., Oka A., Taniguchi M., Ida H., Eto Y., Ogawa S., Matsuzaki Y., Sawa M., Inoue T., Higaki K., Nanba E., Ohno K., Suzuki Y.: "N-Octyl-β-valienamine up-regulates activity of F213I mutant β-glucosidase in cultured cells : a potential chemical chaperone therapy for Gaucher disease."Biochim.Biophys.Acta. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Ohara S., Ukita Y., Ninomiya H., Ohno K.: "Neuroaxonal dystrophy of the dorsal root ganglion sensory neurons in Niemann-Pick disease type C model mouse."Exp.Neurol.. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kato Y., Akai A., Suzuki R., Hosokawa H., Ninomiya H., Masaki T., Nagata K., Tanokura M: "^1H, ^<13>C and ^<15>N assignments of the tandem WW domains of human MAGI-1/BAP-1."J.Biomol.NMR. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Ohsaki Y., Sugimoto Y., Suzuki M., Kaidoh T., Shimada Y., Ohno-Iwashita Y., Davies J.P., Ioannou Y.A., Ohno K., Ninomiya H.: "Reduced sensitivity of Niemann-Pick C1-deficient cells to θ-toxin (perfringolysin O) : sequestration of toxin to raft-enriched membrane vesicles."Histochem.Cell Biol.. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Wakutani Y., Watanabe K., Adachi Y., Wada-Isoe K., Urakami K., Ninomiya H., Ohno K., Saido T.C., Hashimoto T., Iwatsubo T., Nakashima K.: "Novel amyloid precursor protein gene missense mutation (D678N) in familial Alzheimer's disease."J.Neurol.Neurosurg.Psychiat. (in press). (2004)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Feng J.H., Yamamoto T., Nanba E., Ninomiya H., Oka A., Ohno K.: "Novel TSC2 mutations and decreased expression of tuberin in cultured tumor cells with an insertion mutation."Hum.Mutat.. 24. 397 (2004)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Matsuzawa F., Aikawa S.I., Sakuraba H., Tanaka A., Ohno K., Ninomiya H., Sugimoto Y., Doi H.: "Structural basis of GM2 gangliosidosis B variant."J.Hum.Genet.. 48. 582-589 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Pipo J.R., Feng J.H., Yamamoto T., Ohsaki Y., Nanba E., Taujino S., Sakuragawa N., Martiniuk F., Ninomiya H., Oka A., Ohno K.: "New GAA mutations in Japanese patients with GSDII (pompe disease)."Pediatr Neurol.. 29. 284-287 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sugii S., Reid P.C., Ohgami N., Shimada Y., Maue R.A., Ninomiya H., Ohno-Iwashita Y., Chang T.Y.: "Biotinylated theta-toxin derivative as a probe to examine intracellular cholesterol-rich domains in normal and Niemann-Pick type C1 cells."J.Lipid Res.. 44. 1033-1041 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kitamura Y, Ninomiya H: "Smad expression of hepatic satellite cells in liver cirrhosis in vivo and hepatic satellite cell lines in vitro."Pathol.Int.. 53. 18-26 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Hosokawa H., Ninomiya H., Kitamura Y., Fujiwara K., Masaki T.: "Vascular endothelial cells that express dystroglycan are involved in angiogenesis."J.Cell Sci.. 115. 1487-1496 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kato Y.他: "^1H, ^<13>C and ^<15>N assignments of the tandem WW domains of human MAGI-1/BAP-1."J.Biomol.NMR. (印刷中). (2004)
• [Publications] Ohsaki Y.他: "Reduced sensitivity of Niemann-Pick Cl-deficient cells to θ-toxin (perfringolysinO) : sequestration of toxin to raft-enriched membrane vesicles."Histochem.Cell Biol.. (印刷中). (2004)
• [Publications] Wakutani Y.他: "Novel amyloid precursor protein gene missense mutation (D678N) in familial Alzheimer's disease."J.Neurol.Neurosurg.Psychiat.. (印刷中). (2004)
• [Publications] Feng J.H.他: "Novel TSC2 mutations and decreased expression of tuberin in cultured tumor cells with an insertion mutation."Hum.Mutat.. 24. 397 (2004)
• [Publications] Matsuzawa F.他: "Structural basis of GM2 gangliosidosis B variant."J.Hum.Genet.. 48. 582-589 (2003)
• [Publications] Sugii S.他: "Biotinylated theta-toxin derivative as a probe to examine intracellular cholesterol-rich domains in normal and Niemann-Pick type C1 cells."J.Lipid.Res.. 44. 1033-1041 (2003)
• [Publications] Sugii S et al.: "Biotinylated θ-toxin derivative as a probe to examine intracellular cholesterol-rich domains in normal and Niemann-Pick type C1 cells"J. Lipid Res.. (印刷中).