2002 Fiscal Year Annual Research Report

IL-18の多彩な生理活性を可能にするシグナル伝達系の解析

Research Project

Project/Area Number	13670485
Research Institution	HYOGO COLLEGE OF MEDICINE
Principal Investigator	筒井ひろ子兵庫医科大学, 医学部, 助教授 (40236914)
Co-Investigator(Kenkyū-buntansha)	岡村春樹兵庫医科大学, 医学部, 教授 (60111043) 中西憲司兵庫医科大学, 医学部, 教授 (60172350)
Keywords	IL-18 / TH1サイトカイン / TH2サイトカイン / NK活性 / MyD88 / Tyk2 / IL-18受容体 / CD4+ cells
Research Abstract	IL-18受容体はIL-1受容体と、相同性が高く、特に細胞内ドメインの相同性は著しく高い。しかし、IL-1と異なり、IL-18は免疫応答上多様な活性を示す。IL-18はIL-12と共存すると、強力にTh細胞からのIFN-γなどのTh1関連サイトカインの産生を誘導するが、IL-2と共存すると、IL-13やIL-4といったTh2型のサイトカインの産生を促進する。また、IL-18はIL-3と共存すると、マスト細胞や好塩基球からのIL-13やIL-4産生を誘導し、またヒスタミン遊離を促す。さらに、IL-18単独刺激でIL-12が無くても、NK細胞に作用すると、IFN-γ産生を誘導するのみならず、NK細胞活性を増強する。このような多様なIL-18の生理活性が、シグナル伝達系の使い分けに依存するのか否かを検討してきた。NK細胞の障害活性の増強並びに、NK細胞からのIFN-γの産生には、細胞内アダプター分子であるMyD88が必須であることが明らかとなった。また、JAK kinaseの一員であるTyk2も重要な働きを果たしていることが判明した。Tyk2欠損NK細胞をIL-18で刺激しても、IFN-γの産生は、野生型のそれに比べて顕著に低値であった。また、同刺激により、野生型NK細胞はNK活性を亢進して、NK細胞感受性の細胞はより強く傷害された。しかし、Tyk2欠損NK細胞はIL-18刺激に対して、NK活性の亢進が観察されなかった。また、Tyk2欠損CD4陽性細胞は、IL-18とIL-2刺激に対して、IL-4やIL-13をほとんど産生せず、野生型CD4陽性細胞に観られる応答が欠損していることが明らかとなった。以上のことから、Tyk2はIL-18の生理活性発現には必須の分子であることが明らかとなった。ところで、Tyk2を含むJAKはstatを介したシグナル伝達に用いられる。IL-18が関与するstatに関しては、今後とも検討する予定である。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Seki, E., Tsutsui, H., et al.: "Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of Myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1β"J. Immunol.. 166. 2654-2657 (2001)
[Publications] Naka, T., Tsutsui, H., et al.: "SOCS (suppressor of cytokine signaling)-/SSI(stat-induced stat inhibitor)-1-deficient hepatic NKT cells participate in severe hepatits through dysregulated cross-talk inhibition of IFN-g and IL-4 signaling"Immunity. 14. 535-545 (2001)
[Publications] Itoi, H., Fujimori, T., Tsutsui, H., et al.: "Fas ligand-induced, caspase-1-dependent accumulation of interleukin (IL)-18 in mice with acute graft-versus-host disease"Blood. 98. 235-237 (2001)
[Publications] Tanaka, T., Tsutsui, H., et al.: "Interleukin-18 is elevated in the sera from patients with atopic dermatitis and from atopic dermatitis model mice, NC/Nga"Int. Arc. Allergy Immunol.. 125. 236-240 (2001)
[Publications] Adachi, K., Tsutsui, H., et al.: "Plasmodium berghei infection in mice induces liver injury by an IL-12-and Toll-like receptor/myeloid differentiation factor 88-dependent mechanism"J. Immunol.. 167. 5928-5934 (2001)
[Publications] Iwasaki, T., Yamashita, K., Tsujimura, T., Kashiwamura, S., Tsutsui, H., et al.: "Interleukin-18 inhibits osteolytic bone metastasis by human lung cancer cells possibly through suppression of osteoclastic bone-resorption in nude mice"J. Immunotherapy. 25. S52-S60 (2002)
[Publications] Shimoda, K., Tsutsui, H., et al.: "Partial impairment of IL-12 and IL-18 signaling in Tyk2-deficient mice"Blood. 99. 2094-2099 (2002)
[Publications] Konishi, H., Tsutsui, H., et al.: "IL-18 contributes to the development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions"Proc. Nati. Acad. Sci. USA. 99. 11340-11345 (2002)
[Publications] Fujimori, T, et al.: "Increased expression of interleukin 18 receptor on T lymphocytes in patients with acute graft-versus-host disease after allogeneic bone marrow transplantation"J. Interferon Cytokine Res.. 22. 751-754 (2002)
[Publications] Seki, E., Tsutsui, H., et al.: "Critical roles of MyD88-dependent proinflammatory cytokine release in early phase clearance of Listeria monocyto genes"J. Immunol.. 169. 3863-3868 (2002)
[Publications] Fujimoto, M., Tsutsui, H., et al.: "A regulatory role for suppressor of cytokine signaling-1 in Th polarization in vivo"Int. Immunol.. 14. 1343-1350 (2002)
[Publications] Nakagawa, R., Naka, T., Tsutsui, H., et al.: "SOCS-1 participates in negative regulation of LPS responses"Immunity. 17. 677-687 (2002)
[Publications] Nakano, H., Tsutsui, H., et al.: "Persistent secretion of IL-18 in the skin contributes to IgE response in mice"Int. Immunol.. 15(In Press). (2003)
[Publications] Nakamoto, y., Kaneko, S., Fan, H., Momooi, T., Tsutsui, H., et al.: "Prevention of hepatocellular carcinoma development associated with chronic hepatitis by anti-Fas ligand antibody therapy"J. Exp. Med.. 196. 1105-1111 (2002)
[Publications] Nakanishi, K., Yoshimoto, T., Tsutsui, H., Okamura, H.: "Annu. Rev. Immunol."Annual Reviews, Inc. 839 (2001)
[Publications] 筒井ひろ子, 中西憲司: "免疫学コア講義(木本雅夫,阪口薫雄,山下優毅編)"南山堂. 335 (2002)

2002 Fiscal Year Annual Research Report

IL-18の多彩な生理活性を可能にするシグナル伝達系の解析

Principal Investigator

筒井 ひろ子 兵庫医科大学, 医学部, 助教授 (40236914)

Research Products

[Publications] Seki, E., Tsutsui, H., et al.: "Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of Myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1β"J. Immunol.. 166. 2654-2657 (2001)

[Publications] Naka, T., Tsutsui, H., et al.: "SOCS (suppressor of cytokine signaling)-/SSI(stat-induced stat inhibitor)-1-deficient hepatic NKT cells participate in severe hepatits through dysregulated cross-talk inhibition of IFN-g and IL-4 signaling"Immunity. 14. 535-545 (2001)

[Publications] Itoi, H., Fujimori, T., Tsutsui, H., et al.: "Fas ligand-induced, caspase-1-dependent accumulation of interleukin (IL)-18 in mice with acute graft-versus-host disease"Blood. 98. 235-237 (2001)

[Publications] Tanaka, T., Tsutsui, H., et al.: "Interleukin-18 is elevated in the sera from patients with atopic dermatitis and from atopic dermatitis model mice, NC/Nga"Int. Arc. Allergy Immunol.. 125. 236-240 (2001)

[Publications] Adachi, K., Tsutsui, H., et al.: "Plasmodium berghei infection in mice induces liver injury by an IL-12-and Toll-like receptor/myeloid differentiation factor 88-dependent mechanism"J. Immunol.. 167. 5928-5934 (2001)

[Publications] Iwasaki, T., Yamashita, K., Tsujimura, T., Kashiwamura, S., Tsutsui, H., et al.: "Interleukin-18 inhibits osteolytic bone metastasis by human lung cancer cells possibly through suppression of osteoclastic bone-resorption in nude mice"J. Immunotherapy. 25. S52-S60 (2002)

[Publications] Shimoda, K., Tsutsui, H., et al.: "Partial impairment of IL-12 and IL-18 signaling in Tyk2-deficient mice"Blood. 99. 2094-2099 (2002)

[Publications] Konishi, H., Tsutsui, H., et al.: "IL-18 contributes to the development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions"Proc. Nati. Acad. Sci. USA. 99. 11340-11345 (2002)

[Publications] Fujimori, T, et al.: "Increased expression of interleukin 18 receptor on T lymphocytes in patients with acute graft-versus-host disease after allogeneic bone marrow transplantation"J. Interferon Cytokine Res.. 22. 751-754 (2002)

[Publications] Seki, E., Tsutsui, H., et al.: "Critical roles of MyD88-dependent proinflammatory cytokine release in early phase clearance of Listeria monocyto genes"J. Immunol.. 169. 3863-3868 (2002)

[Publications] Fujimoto, M., Tsutsui, H., et al.: "A regulatory role for suppressor of cytokine signaling-1 in Th polarization in vivo"Int. Immunol.. 14. 1343-1350 (2002)

[Publications] Nakagawa, R., Naka, T., Tsutsui, H., et al.: "SOCS-1 participates in negative regulation of LPS responses"Immunity. 17. 677-687 (2002)

[Publications] Nakano, H., Tsutsui, H., et al.: "Persistent secretion of IL-18 in the skin contributes to IgE response in mice"Int. Immunol.. 15(In Press). (2003)

[Publications] Nakamoto, y., Kaneko, S., Fan, H., Momooi, T., Tsutsui, H., et al.: "Prevention of hepatocellular carcinoma development associated with chronic hepatitis by anti-Fas ligand antibody therapy"J. Exp. Med.. 196. 1105-1111 (2002)

[Publications] Nakanishi, K., Yoshimoto, T., Tsutsui, H., Okamura, H.: "Annu. Rev. Immunol."Annual Reviews, Inc. 839 (2001)

[Publications] 筒井ひろ子, 中西憲司: "免疫学コア講義(木本雅夫,阪口薫雄,山下優毅 編)"南山堂. 335 (2002)

筒井ひろ子兵庫医科大学, 医学部, 助教授 (40236914)

[Publications] 筒井ひろ子, 中西憲司: "免疫学コア講義(木本雅夫,阪口薫雄,山下優毅編)"南山堂. 335 (2002)