2003 Fiscal Year Annual Research Report

Toll-like receptorによるT細胞の活性化と感染防御機構での役割

Research Project

Project/Area Number	14370091
Research Institution	Kyushu University
Principal Investigator	吉開泰信九州大学, 生体防御医学研究所, 教授 (90158402)
Keywords	Toll-like receptor / NKT細胞 / サルモネラ感染 / 肝臓傷害 / Fas-L / JNK / 胆管結紮 / JIP3
Research Abstract	(1)大腸菌をマウスに感染させると感染12時間目をピークとする肝障害が誘導された。NKT細胞が特異的に欠損しているマウス(Jα 281 KOマウス)では,肝障害はほとんど認められず,またToll-like receptor(TLR)2欠損マウス、FasL変異gld/gldマウスでは,肝障害は有意に減弱していた。TLR2のリガンドであるリポ蛋白で、ナイーブマウスのNKT細胞をin vitroで刺激するとFasLの発現が誘導された。これらの結果から、大腸菌感染よる肝障害の系では,NKT細胞のTLR2に対するリポ蛋白刺激がFasLを誘導して肝障害をもたらすと考えられる。(Eur.J.Immuno1.33:2511-9.2003) (2)胆管結紮マウスでは結紮後早期に肝障害が認められる。この肝障害はNKT細胞が特異的に欠損しているマウス(Jα 281 KOマウス)では,ほとんど認められず,またTLR2欠損マウス、FasL変異gld/gldマウスでは,肝障害は有意に減弱していた。ナイーブマウスのNKT細胞を胆汁酸の成分でin vitroで刺激するとFasLの発現が誘導された。これらの結果から、胆管結紮よる肝障害の系でも,TLR2発現NKT細胞が重要な役割を担っていると考えられる。(Hepatology in press 2004) (3)TLR-4からのシグナル伝達機構を明らかにするためにTLR-4の細胞内ドメインをbaitとしてtwo hybrid法にてscafold proteinであるJIP3をクローニングした。JIP3の過剰発現ではリポ多糖体(LPS)刺激によるJNK活性化が増強し、逆にJIP3のRNA interferenceによるJIP3発現抑制は、LPS刺激によるJNK活性化が阻害された。JIP3にはMEKK-1が結合していることが明かとなった。さらにJIP3はTLR-2とTLR-9にも結合できることがわかった。(EMBO J 22:4455-64,2003)。

Research Products

(13 results)

All Other

All Publications (13 results)

[Publications] Ishimitsu, R.et al.: "NKT cells are dispensable in induction of oral tolerance but indispensable in abrogation of oral tolerance by prostaglandin E"Eur.J.Immunol. 33. 183-193 (2003)
[Publications] Musikacharoen, T.et al.: "Histone acetylation and activation of CREB regulate transcriptional activation of MKP-M in LPS-stimulated macrophages"J.Biol Chem.. 278. 9167-9175 (2003)
[Publications] Hiromatsu, T.et al.: "Overexpression of IL-15 protects against Escherichia coli-induced shock accompanied by inhibition of TNF-α-induced apoptosis"J.Infect.Dis.. 187. 1442-1451 (2003)
[Publications] Matsuguchi, T.et al.: "JNK-interacting protein 3 associates with Toll-like receptor 4 and is involved in LPS-mediated JNK activation"EMBO J.. 22. 4455-4464 (2003)
[Publications] Hiromatsu, T.et al.: "NK T cells stimulated with a ligand for TLR2 contribute to liver injury caused by Escherichia coli infection in mice"Eur.J.Immunol.. 33. 2511-2519 (2003)
[Publications] Saito, K.et al.: "Soluble branched (1,4)-β-D-glucans from Acetobacter species show strong activities to induce IL-12 in vitro and inhibit Th2 response with IgE production in vivo"J Biol Chem.. 278. 38571-38578 (2003)
[Publications] Umemura, M.et al.: "Interleukin-15 as an immune adjuvant to increase efficacy of Bacillus Calmette-Guerin vaccination"Infect.Immun.. 71. 6045-6048 (2003)
[Publications] Kikuchi, T.et al.: "Cot/Tp12 is essential for RANKL induction by lipid A in osteoblasts"J.Dent.Res.. 82. 542-545 (2003)
[Publications] Matsuguchi, T.et al.: "Lipoteichoic acids from Lactobacillus strains elicit strong tumor necrosis factor alpha-Inducing activities in macrophages through Toll-like receptor 2"Clin.Diagn.Lab.Immunol.. 10. 259-266 (2003)
[Publications] Abe, T.et al.: "Predominant IL-10 production by Kupffer cells is responsible for impaired bacterial clearance in mice with obstructive cholestasis"Hepatology. In press. (2004)
[Publications] Yajima, T.et al.: "Overexpression of IL-15 increases susceptibility to lethal endotoxic shock in mice primed with Mycobacterium bovis BCG"Infect.Immun.. In press. (2004)
[Publications] Nishimura, H.et al.: "Intraepithelilal γδ T cells may bridge a gap between innate and acquired immunity to herpes simplex virus type 2"J.Virol. In press. (2004)
[Publications] 吉開泰信: "ウイルス・細菌と感染症がわかる"羊土社. 133 (2003)

2003 Fiscal Year Annual Research Report

Toll-like receptorによるT細胞の活性化と感染防御機構での役割

Principal Investigator

吉開 泰信 九州大学, 生体防御医学研究所, 教授 (90158402)

Research Products

[Publications] Ishimitsu, R.et al.: "NKT cells are dispensable in induction of oral tolerance but indispensable in abrogation of oral tolerance by prostaglandin E"Eur.J.Immunol. 33. 183-193 (2003)

[Publications] Musikacharoen, T.et al.: "Histone acetylation and activation of CREB regulate transcriptional activation of MKP-M in LPS-stimulated macrophages"J.Biol Chem.. 278. 9167-9175 (2003)

[Publications] Hiromatsu, T.et al.: "Overexpression of IL-15 protects against Escherichia coli-induced shock accompanied by inhibition of TNF-α-induced apoptosis"J.Infect.Dis.. 187. 1442-1451 (2003)

[Publications] Matsuguchi, T.et al.: "JNK-interacting protein 3 associates with Toll-like receptor 4 and is involved in LPS-mediated JNK activation"EMBO J.. 22. 4455-4464 (2003)

[Publications] Hiromatsu, T.et al.: "NK T cells stimulated with a ligand for TLR2 contribute to liver injury caused by Escherichia coli infection in mice"Eur.J.Immunol.. 33. 2511-2519 (2003)

[Publications] Saito, K.et al.: "Soluble branched (1,4)-β-D-glucans from Acetobacter species show strong activities to induce IL-12 in vitro and inhibit Th2 response with IgE production in vivo"J Biol Chem.. 278. 38571-38578 (2003)

[Publications] Umemura, M.et al.: "Interleukin-15 as an immune adjuvant to increase efficacy of Bacillus Calmette-Guerin vaccination"Infect.Immun.. 71. 6045-6048 (2003)

[Publications] Kikuchi, T.et al.: "Cot/Tp12 is essential for RANKL induction by lipid A in osteoblasts"J.Dent.Res.. 82. 542-545 (2003)

[Publications] Matsuguchi, T.et al.: "Lipoteichoic acids from Lactobacillus strains elicit strong tumor necrosis factor alpha-Inducing activities in macrophages through Toll-like receptor 2"Clin.Diagn.Lab.Immunol.. 10. 259-266 (2003)

[Publications] Abe, T.et al.: "Predominant IL-10 production by Kupffer cells is responsible for impaired bacterial clearance in mice with obstructive cholestasis"Hepatology. In press. (2004)

[Publications] Yajima, T.et al.: "Overexpression of IL-15 increases susceptibility to lethal endotoxic shock in mice primed with Mycobacterium bovis BCG"Infect.Immun.. In press. (2004)

[Publications] Nishimura, H.et al.: "Intraepithelilal γδ T cells may bridge a gap between innate and acquired immunity to herpes simplex virus type 2"J.Virol. In press. (2004)

[Publications] 吉開泰信: "ウイルス・細菌と感染症がわかる"羊土社. 133 (2003)

吉開泰信九州大学, 生体防御医学研究所, 教授 (90158402)