2002 Fiscal Year Annual Research Report

セリンプロテアーゼインヒビターによる免疫制御機構の解明と治療への応用

Research Project

Project/Area Number	13670461
Research Institution	Nagasaki University
Principal Investigator	江口勝美長崎大学, 大学院・医歯薬学総合研究科, 教授 (30128160)
Co-Investigator(Kenkyū-buntansha)	川上純長崎大学, 大学院・医歯薬学総合研究科, 助手 (90325639)
Keywords	アポトーシス / NK細胞 / グランザイムB / セリンプロテアーゼインヒビター / PI-9 / 関節リウマチ / マクロファージ様滑膜細胞 / PI-1β
Research Abstract	1.NK細胞のアポトーシスとSerpin PI-9の制御機構の解明ヒト末梢血由来NK細胞にactivation-induced cell death(AICD)を誘導すると、1時間後に約50%のNK細胞のミトコンドリア膜電位の低下がみられた。AICD誘導1時間後以降にcaspase3の切断がみられたのに対して、Bidは2分以内に、caspase9は15分後から切断された。免疫沈降法、免疫染色法の検討でアポトーシス誘導1分以内にgranzyme Bとその特異的インヒビターPI-9分子とは複合体を形成しており、AICD誘導によってgranzyme Bが穎粒から漏出することが証明された。NK細胞内のgranzyme B/PI-9比とアポトーシス誘導率とは相関することから、NK細胞のアポトーシスは、NK細胞内における両者の蛋白量のバランスに規定されている可能性が示唆された。NK細胞のアポトーシスはAICD誘導に伴い、granzyme Bが穎粒から漏出、PI-9分子で中和できなかった過剰なgranzyme Bが、Bidを介したミトコンドリアの系を活性化する結果生じる可能性がある。 2.RAにおけるSerpin PI-9制御機構の解明人工関節置換術施行RA患者から得られた滑膜を使用してIL-1β、IL-18産生能を検討した。1)RA患者の滑膜局所においてIL-1βおよびIL-18産生がみられた。2)RA患者の滑膜局所においてPI-9分子、caspase1分子発現がみられた。3)RA患者の滑膜局所におけるIL-1β産生は、caspase1/PI-9比に比例して増加していた。4)RA患者の滑膜組織において、PI-9分子はマクロファージ様滑膜細胞を中心に染色された。以上から、滑膜細胞中のPI-9分子によりIL-1β産生が制御されている可能性がある。

Research Products

(27 results)

All Other

All Publications (27 results)

[Publications] Ida H: "Granzyme B leakage-induced cell death : a new type of activation-induced natural killer cell death"J Immunol. (accepted).
[Publications] Kita-Furuyama M: "Dendritic cells infected with adenovirus expressing the thyrotrophin receptor induce Graves' hyperthyroidism in BALB/c mice"Clin Exp Immunol. 131. 234-240 (2003)
[Publications] Yanagi K: "Immuno-gene therapy with adenoviruses expressing fms-like tyrosine kinase 3 ligand and CD40 ligand for mouse hepatoma cells in vivo"Int J Oncol. 22. 345-351 (2003)
[Publications] Ida H: "Increased levels of interleukin-18 (IL-18) in patients with systemic lupus erythematosus : Comment on the article by Shibatomi et al., Reply to the editor"Arthritis Rheum. 45・5. 1411-1412 (2002)
[Publications] Yamasaki S: "Functional changes in rheumatoid fibroblast-like synovial cells through activation of peroxisome proliferator-activated receptor γ-mediated signalling"Clin Exp Immunol. 129・2. 379-384 (2002)
[Publications] Kawakami A: "Modulation of the expression of membrane-bound CD54 (mCD54) and soluble form of CF54 (sCD54) in endothelial cells by glucosyl transferase inhibitor"Biochem Biophys Res commun. 296・1. 26-31 (2002)
[Publications] Ide A: "Genetic association between interleukin-10 gene promoter region polymorphisms and type 1 diabetes age-at-onset"Hum Immunol. 63・8. 690-695 (2002)
[Publications] Kawakami A: "Involvement of apoptotic cell death in autoimmune diseases"Med Electron Microsc. 35・1. 1-8 (2002)
[Publications] Ueki Y: "NOR-1 : a nitric oxide releasing agent for calibrating low levels of nitric oxide by the chemiluminescence method"Blood Coagul Fibrinolysis. 13・2. 75-80 (2002)
[Publications] Migita K: "The role of peroxynitrite in cyclooxygenase-2 expression of rheumatoid synovium"Clin Exp Rheumatol. 20・1. 59-62 (2002)
[Publications] Nagayama Y: "A novel murine model of Graves' hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor"J Immunol. 168・6. 2789-2794 (2002)
[Publications] Kamachi M: "Regulation of apoptotic cell death by cytokines in a human salivary gland cell line : distinct and synergistic mechanisms in apoptosis induced by tumor necrosis factor α and interferon γ"J Lab Clin Med. 139・1. 13-19 (2002)
[Publications] Yonetsu K: "Sonography as a replacement for sialography for the diagnosis of salivary glands affected by sjogren's syndrome"Ann Rheum Dis. 61・3. 276-277 (2002)
[Publications] Hashimoto Y: "Novel immunosuppressive effect of FK506 by augmentation of T cell apoptosis"Clin Exp Immunol. 125. 19-24 (2001)
[Publications] Eguchi K: "A poptosis in autoimmune diseases"Internal Med. 40・4. 275-284 (2001)
[Publications] Sera N: "Fas-FasL mediated apoptosis of thyrocytes in Graves' disease"Clin Exp Immunol. 124. 197-207 (2001)
[Publications] Hamasaki S: "Resistance of CD4-positive T lymphocytes to etoposide-induced apoptosis mediated by upregulation of Bcl-xL expression in patients with HTLV-I-associated myelopathy"J Neuroimmunol. 117. 143-148 (2001)
[Publications] Hirai Y: "Effects of nitric oxide on matrix metalloproteinase-2 production by rheumatoid synovial cells"Life Sci. 68. 913-920 (2001)
[Publications] Migita K: "Impaired degradation of serum amyloid A (SAA) protein by cytokine-stimulated monocytes"Clin Exp Immunol. 123・3. 408-411 (2001)
[Publications] Shibatomi K: "A Novel Role for Interleukin-18 in Human Natural Killer Cell Death"Arthritis Rheum. 44・4. 884-892 (2001)
[Publications] Kawakami A: "Role of HTLV-I infection in the pathogenesis of Sjoren's Syndrome and rheumatoid arthritis"Mod Rheumatol. 11・2. 87-90 (2001)
[Publications] Migita K: "FK506-Mediated T-Cell Apoptosis Induction"Transplant P. 33. 2292-2293 (2001)
[Publications] Yamasaki S: "Importance of NF-κB in rheumatoid synovial tissues : in situ NF-κB expression and in vitro study using cultured synovial cells"Ann Rheum Dis. 60・7. 678-684 (2001)
[Publications] Migita K: "Nitric oxide protects cultured rheumatoid synovial cells from Fas-Induced Apoptosis by inhibiting caspase-3"Immunology. 103. 362-367 (2001)
[Publications] Migita K: "Regulation of rheumatoid synoviocyte proliferation by endogenous p53 induction"Clin Exp Immunol. 126・2. 334-338 (2001)
[Publications] Urayama S: "New disease-modifying antirheumatic drug 2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid(KE-298) selectively augments activation-induced T cell death"J Lab Clin Med. 138. 11-17 (2001)
[Publications] Migita K: "Mechanistic Differences of Cornerstone Immunosuppressants"Fujisawa. 6 (2001)

2002 Fiscal Year Annual Research Report

セリンプロテアーゼインヒビターによる免疫制御機構の解明と治療への応用

Principal Investigator

江口 勝美 長崎大学, 大学院・医歯薬学総合研究科, 教授 (30128160)

Research Products

[Publications] Ida H: "Granzyme B leakage-induced cell death : a new type of activation-induced natural killer cell death"J Immunol. (accepted).

[Publications] Kita-Furuyama M: "Dendritic cells infected with adenovirus expressing the thyrotrophin receptor induce Graves' hyperthyroidism in BALB/c mice"Clin Exp Immunol. 131. 234-240 (2003)

[Publications] Yanagi K: "Immuno-gene therapy with adenoviruses expressing fms-like tyrosine kinase 3 ligand and CD40 ligand for mouse hepatoma cells in vivo"Int J Oncol. 22. 345-351 (2003)

[Publications] Ida H: "Increased levels of interleukin-18 (IL-18) in patients with systemic lupus erythematosus : Comment on the article by Shibatomi et al., Reply to the editor"Arthritis Rheum. 45・5. 1411-1412 (2002)

[Publications] Yamasaki S: "Functional changes in rheumatoid fibroblast-like synovial cells through activation of peroxisome proliferator-activated receptor γ-mediated signalling"Clin Exp Immunol. 129・2. 379-384 (2002)

[Publications] Kawakami A: "Modulation of the expression of membrane-bound CD54 (mCD54) and soluble form of CF54 (sCD54) in endothelial cells by glucosyl transferase inhibitor"Biochem Biophys Res commun. 296・1. 26-31 (2002)

[Publications] Ide A: "Genetic association between interleukin-10 gene promoter region polymorphisms and type 1 diabetes age-at-onset"Hum Immunol. 63・8. 690-695 (2002)

[Publications] Kawakami A: "Involvement of apoptotic cell death in autoimmune diseases"Med Electron Microsc. 35・1. 1-8 (2002)

[Publications] Ueki Y: "NOR-1 : a nitric oxide releasing agent for calibrating low levels of nitric oxide by the chemiluminescence method"Blood Coagul Fibrinolysis. 13・2. 75-80 (2002)

[Publications] Migita K: "The role of peroxynitrite in cyclooxygenase-2 expression of rheumatoid synovium"Clin Exp Rheumatol. 20・1. 59-62 (2002)

[Publications] Nagayama Y: "A novel murine model of Graves' hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor"J Immunol. 168・6. 2789-2794 (2002)

[Publications] Kamachi M: "Regulation of apoptotic cell death by cytokines in a human salivary gland cell line : distinct and synergistic mechanisms in apoptosis induced by tumor necrosis factor α and interferon γ"J Lab Clin Med. 139・1. 13-19 (2002)

[Publications] Yonetsu K: "Sonography as a replacement for sialography for the diagnosis of salivary glands affected by sjogren's syndrome"Ann Rheum Dis. 61・3. 276-277 (2002)

[Publications] Hashimoto Y: "Novel immunosuppressive effect of FK506 by augmentation of T cell apoptosis"Clin Exp Immunol. 125. 19-24 (2001)

[Publications] Eguchi K: "A poptosis in autoimmune diseases"Internal Med. 40・4. 275-284 (2001)

[Publications] Sera N: "Fas-FasL mediated apoptosis of thyrocytes in Graves' disease"Clin Exp Immunol. 124. 197-207 (2001)

[Publications] Hamasaki S: "Resistance of CD4-positive T lymphocytes to etoposide-induced apoptosis mediated by upregulation of Bcl-xL expression in patients with HTLV-I-associated myelopathy"J Neuroimmunol. 117. 143-148 (2001)

[Publications] Hirai Y: "Effects of nitric oxide on matrix metalloproteinase-2 production by rheumatoid synovial cells"Life Sci. 68. 913-920 (2001)

[Publications] Migita K: "Impaired degradation of serum amyloid A (SAA) protein by cytokine-stimulated monocytes"Clin Exp Immunol. 123・3. 408-411 (2001)

[Publications] Shibatomi K: "A Novel Role for Interleukin-18 in Human Natural Killer Cell Death"Arthritis Rheum. 44・4. 884-892 (2001)

[Publications] Kawakami A: "Role of HTLV-I infection in the pathogenesis of Sjoren's Syndrome and rheumatoid arthritis"Mod Rheumatol. 11・2. 87-90 (2001)

[Publications] Migita K: "FK506-Mediated T-Cell Apoptosis Induction"Transplant P. 33. 2292-2293 (2001)

[Publications] Yamasaki S: "Importance of NF-κB in rheumatoid synovial tissues : in situ NF-κB expression and in vitro study using cultured synovial cells"Ann Rheum Dis. 60・7. 678-684 (2001)

[Publications] Migita K: "Nitric oxide protects cultured rheumatoid synovial cells from Fas-Induced Apoptosis by inhibiting caspase-3"Immunology. 103. 362-367 (2001)

[Publications] Migita K: "Regulation of rheumatoid synoviocyte proliferation by endogenous p53 induction"Clin Exp Immunol. 126・2. 334-338 (2001)

[Publications] Urayama S: "New disease-modifying antirheumatic drug 2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid(KE-298) selectively augments activation-induced T cell death"J Lab Clin Med. 138. 11-17 (2001)

[Publications] Migita K: "Mechanistic Differences of Cornerstone Immunosuppressants"Fujisawa. 6 (2001)

江口勝美長崎大学, 大学院・医歯薬学総合研究科, 教授 (30128160)