1994 Fiscal Year Annual Research Report

インターロイキン2(IL-2)の作用を標的とした免疫抑制剤の開発

Research Project

Project/Area Number	05557022
Research Institution	Tohoku University
Principal Investigator	菅村和夫東北大学, 医学部, 教授 (20117360)
Co-Investigator(Kenkyū-buntansha)	里見進東北大学, 医学部, 講師 (00154120) 佐々木毅東北大学, 医学部, 教授 (50110656) 浅尾裕信東北大学, 医学部, 助手 (80250744)
Keywords	免疫制御 / サイトカイン / IL-2受容体 / γ鎖 / 可溶化型
Research Abstract	T細胞増殖因子であるインターロイキン2(IL-2)の機能的受容体は少なくともα鎖、β鎖、γ鎖の3種のサブユニットよりなる。β鎖とγ鎖はシグナル伝達に必須で、IL-2刺激により、ともに、早期にチロシンリン酸化される。IL-2受容体からのシグナル伝達機構を解明するため、IL-2受容体複合体に会合するチロシンキナーゼの同定と、β鎖・γ鎖の細胞質内領域のうちシグナル伝達に必要な領域を、β鎖・γ鎖の変異体を用いて解析した。抗β鎖抗体(TU11)による免疫沈降物中にJAK1チロシンキナーゼ分子が含まれ、抗γ鎖抗体(TUGh4)の免疫沈降物にJAK3が含まれていることを見い出した。これらの共沈はIL-2の存在にかかわりなく認められた。また、IL-2刺激により、JAK1、JAK3ともチロシンリン酸化され、IL-2刺激によりこれらのチロシンキナーゼが活性化されるものと考えられた。γ鎖の変異体のうち、カルボキシ末端30アミノ酸残基を欠失したものは正常なγ鎖と同様、JAK3の会合もIL-2によるチロシンリン酸化も認められたが、カルボキシ末端68アミノ酸残基を欠失したものや、SH2様領域を欠失した変異体ではJAK3の会合もリン酸化も見られなかった。serine rich領域を欠失したβ鎖はJAK1の会合もIL-2によるチロシンリン酸化もみられず、一方acidic領域を欠失したβ鎖は、正常β鎖と同様であった。IL-2による細胞増殖はJAK1、JAK3のチロシンリン酸化をよく相関しており、β鎖のserine rich領域とγ鎖のSH様領域はJAK分子を介して増殖に必須なシグナルを発信していると考えられる。

Research Products
(17 results)

All Other

All Publications (17 results)

[Publications] Kondo,M.: "Functional participation of the IL-2 receptor γ chain in IL-7 receptor complexes." Science. 263. 1453-1454 (1994)
[Publications] Roessler,E.: "Cooperative interactions between the interleukin 2 recepotr α and β chains alter the interleukin 2-binding affinity of the receptor subunits." Proc.Natl.Acad.Sci USA. 91. 3344-3347 (1994)
[Publications] Vanham,G.: "The interleukin-2 receptor subunit expression and function on peripheral blood lymphocytes from HIV-infected and control persons." Clin.Immunol Immunopathol.71. 60-68 (1994)
[Publications] Ishii,N.: "Impairment of ligand binding and growth signaling of mutant IL-2 receptor γ chains in patients with X-linked severe combined immunodeficiency." J.Immunol.153. 1310-1317 (1994)
[Publications] Tanaka,N.: "Physical association of JAK1 and JAK2 tyrosine kinases with the interleukin 2 receptor β and γ chains." Proc.Natl.Acad.Sci.USA. 91. 7271-7275 (1994)
[Publications] Ishii,N.: "Expressin of the interleukin 2 receptor γ chain on various populations in human peripheral blood." Inter.Immunol.6. 1273-1277 (1994)
[Publications] Asao,H.: "Interleukin 2-induced activation of JAK3:possible involvement in signal transduction for c-mycinduction and cell proliferation." FEBS Letters. 351. 201-206 (1994)
[Publications] Kondo,M.: "Expression of the mouse interleukin-2 receptor γ chain in various cell populations of thymus and spleen." Eur.J.Immunol.24. 2026-2030 (1994)
[Publications] Hozumi,K.: "Implication of the common γ chain of the IL-7 receptor in intrathymic development of pro-T cells." Inter.Immunol.6. 1451-1454 (1994)
[Publications] Yaegashi,N.: "The frequency of human parvovirus B19 infection in nonimmune hydrops fatalis." J.Perinatal Medicine.22. 159-163 (1994)
[Publications] Asano,M.: "Interleukin-2can support growth of CD8+T cells but not CD4+T cells of human IL-2 receptor β chain transgeneic mice." J.Immunol.153. 5373-5381 (1994)
[Publications] Bosco,M.C.: "Regulation by interleukin-2(IL-2)and interferon γ of of IL-2 receptor γ chain gene expression in human monocytes." Blood. 83. 2995-3002 (1994)
[Publications] Minegishi,Y.: "Preferential utilization of immature JH segment and absence of somatic mutation in CDR3 junction of Ig H chain gene in three X-Iinked severe combined immunodeficiency patients." Inter.Immunol.in press.
[Publications] Kimura,Y.: "Sharing of the IL-2 receptor γ chain with the functionall IL-9 receptor complex." Inter.Immunol.,in press.
[Publications] Watanabe,S.: "Involvement of the IL-2 receptor γ sudunit in IL-4 dependent activation of mouse hematopoietic cells and splenic B cells." Eur.J.Immunol.in press.
[Publications] Ohbo,K.: "Functional analysis for the human interleukin 2 receptor γ chain gene promoter." J,Biol.Chem.in press.
[Publications] Sugamura,K.: "The common γ chain of multiple cytokine receptors." Adv.Immunol.in press.

1994 Fiscal Year Annual Research Report

インターロイキン2(IL-2)の作用を標的とした免疫抑制剤の開発

Principal Investigator

菅村 和夫 東北大学, 医学部, 教授 (20117360)

Research Products

[Publications] Kondo,M.: "Functional participation of the IL-2 receptor γ chain in IL-7 receptor complexes." Science. 263. 1453-1454 (1994)

[Publications] Roessler,E.: "Cooperative interactions between the interleukin 2 recepotr α and β chains alter the interleukin 2-binding affinity of the receptor subunits." Proc.Natl.Acad.Sci USA. 91. 3344-3347 (1994)

[Publications] Vanham,G.: "The interleukin-2 receptor subunit expression and function on peripheral blood lymphocytes from HIV-infected and control persons." Clin.Immunol Immunopathol.71. 60-68 (1994)

[Publications] Ishii,N.: "Impairment of ligand binding and growth signaling of mutant IL-2 receptor γ chains in patients with X-linked severe combined immunodeficiency." J.Immunol.153. 1310-1317 (1994)

[Publications] Tanaka,N.: "Physical association of JAK1 and JAK2 tyrosine kinases with the interleukin 2 receptor β and γ chains." Proc.Natl.Acad.Sci.USA. 91. 7271-7275 (1994)

[Publications] Ishii,N.: "Expressin of the interleukin 2 receptor γ chain on various populations in human peripheral blood." Inter.Immunol.6. 1273-1277 (1994)

[Publications] Asao,H.: "Interleukin 2-induced activation of JAK3:possible involvement in signal transduction for c-mycinduction and cell proliferation." FEBS Letters. 351. 201-206 (1994)

[Publications] Kondo,M.: "Expression of the mouse interleukin-2 receptor γ chain in various cell populations of thymus and spleen." Eur.J.Immunol.24. 2026-2030 (1994)

[Publications] Hozumi,K.: "Implication of the common γ chain of the IL-7 receptor in intrathymic development of pro-T cells." Inter.Immunol.6. 1451-1454 (1994)

[Publications] Yaegashi,N.: "The frequency of human parvovirus B19 infection in nonimmune hydrops fatalis." J.Perinatal Medicine.22. 159-163 (1994)

[Publications] Asano,M.: "Interleukin-2can support growth of CD8+T cells but not CD4+T cells of human IL-2 receptor β chain transgeneic mice." J.Immunol.153. 5373-5381 (1994)

[Publications] Bosco,M.C.: "Regulation by interleukin-2(IL-2)and interferon γ of of IL-2 receptor γ chain gene expression in human monocytes." Blood. 83. 2995-3002 (1994)

[Publications] Minegishi,Y.: "Preferential utilization of immature JH segment and absence of somatic mutation in CDR3 junction of Ig H chain gene in three X-Iinked severe combined immunodeficiency patients." Inter.Immunol.in press.

[Publications] Kimura,Y.: "Sharing of the IL-2 receptor γ chain with the functionall IL-9 receptor complex." Inter.Immunol.,in press.

[Publications] Watanabe,S.: "Involvement of the IL-2 receptor γ sudunit in IL-4 dependent activation of mouse hematopoietic cells and splenic B cells." Eur.J.Immunol.in press.

[Publications] Ohbo,K.: "Functional analysis for the human interleukin 2 receptor γ chain gene promoter." J,Biol.Chem.in press.

[Publications] Sugamura,K.: "The common γ chain of multiple cytokine receptors." Adv.Immunol.in press.

菅村和夫東北大学, 医学部, 教授 (20117360)