研究者詳細 - 吉村　昭彦

論文 - 吉村　昭彦

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Membrane molecules mobile even after chemical fixation

Tanaka Kenji A K, Suzuki Kenichi G N, Shirai Yuki M., Shibutani Shusaku T., Miyahara Manami S H, Tsuboi Hisae, Yahara Miyako, Yoshimura Akihiko, Mayor Satyajit, Fujiwara Takahiro K., Kusumi Akihiro

Nature Methods 7 （ 11 ） 865 - 866 2010年11月

ISSN 1548-7091

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Membrane molecules mobile even after chemical fixation

Tanaka Kenji A K, Suzuki Kenichi G N, Shirai Yuki M., Shibutani Shusaku T., Miyahara Manami S H, Tsuboi Hisae, Yahara Miyako, Yoshimura Akihiko, Mayor Satyajit, Fujiwara Takahiro K., Kusumi Akihiro

Nature Methods 7 （ 11 ） 865 - 866 2010年11月

ISSN 1548-7091

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Function of miR-146a in Controlling Treg Cell-Mediated Regulation of Th1 Responses

Lu Li Fan, Boldin Mark P., Chaudhry Ashutosh, Lin Ling Li, Taganov Konstantin D., Hanada Toshikatsu, Yoshimura Akihiko, Baltimore David, Rudensky Alexander Y.

Cell 142 （ 6 ） 914 - 929 2010年09月

ISSN 0092-8674

Foxp3⁺ regulatory T (Treg) cells maintain immune homeostasis by limiting different types of inflammatory responses. Here, we report that miR-146a, one of the miRNAs prevalently expressed in Treg cells, is critical for their suppressor function. The deficiency of miR-146a in Treg cells resulted in a breakdown of immunological tolerance manifested in fatal IFNγ-dependent immune-mediated lesions in a variety of organs. This was likely due to augmented expression and activation of signal transducer and activator transcription 1 (Stat1), a direct target of miR-146a. Likewise, heightened Stat1 activation in Treg cells subjected to a selective ablation of SOCS1, a key negative regulator of Stat1 phosphorylation downstream of the IFNγ receptor, was associated with analogous Th1-mediated pathology. Our results suggest that specific aspects of Treg suppressor function are controlled by a single miRNA and that an optimal range of Stat1 activation is important for Treg-mediated control of Th1 responses and associated autoimmunity. © 2010 Elsevier Inc.

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Function of miR-146a in Controlling Treg Cell-Mediated Regulation of Th1 Responses

Lu Li Fan, Boldin Mark P., Chaudhry Ashutosh, Lin Ling Li, Taganov Konstantin D., Hanada Toshikatsu, Yoshimura Akihiko, Baltimore David, Rudensky Alexander Y.

Cell 142 （ 6 ） 914 - 929 2010年09月

ISSN 0092-8674

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Smad2 and Smad3 are redundantly essential for the TGF-β-mediated regulation of regulatory T plasticity and Th1 development

Takimoto Tomohito, Wakabayashi Yu, Sekiya Takashi, Inoue Naoko, Morita Rimpei, Ichiyama Kenji, Takahashi Reiko, Asakawa Mayako, Muto Go, Mori Tomoaki, Hasegawa Eiichi, Shizuya Saika, Hara Toshiro, Nomura Masatoshi, Yoshimura Akihiko

Journal of Immunology 185 （ 2 ） 842 - 855 2010年07月

ISSN 0022-1767

Although it has been well established that TGF-β plays a pivotal role in immune regulation, the roles of its downstream transcription factors, Smad2 and Smad3, have not been fully clarified. Specifically, the function of Smad2 in the immune system has not been investigated because of the embryonic lethality of Smad2-deficient mice. In this study, we generated T cell-specific Smad2 conditional knockout (KO) mice and unexpectedly found that Smad2 and Smad3 were redundantly essential for TGF-β-mediated induction of Foxp3-expressing regulatory T cells and suppression of IFN-γ production in CD4⁺ T cells. Consistent with these observations, Smad2/Smad3-double KO mice, but not single KO mice, developed fatal inflammatory diseases with higher IFN-γ production and reduced Foxp3 expression in CD4⁺ T cells at the periphery. Although it has been suggested that Foxp3 induction might underlie TGF-β-mediated immunosuppression, TGF-β still can suppress Th1 cell development in Foxp3-deficient T cells, suggesting that the Smad2/3 pathway inhibits Th1 cell development with Foxp3-independent mechanisms. We also found that Th17 cell development was reduced in Smad-deficient CD4⁺ T cells because of higher production of Th17-inhibotory cytokines from these T cells. However, TGF-β-mediated induction of RORγt, a master regulator of Th17 cell, was independent of both Smad2 and Smad3, suggesting that TGF-β regulates Th17 development through Smad2/3-dependent and -independent mechanisms. Copyright © 2010 by The American Association of Immunologists, Inc.

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Smad2 and Smad3 are redundantly essential for the TGF-β-mediated regulation of regulatory T plasticity and Th1 development

Journal of Immunology 185 （ 2 ） 842 - 855 2010年07月

ISSN 0022-1767

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Cellular and molecular basis for the regulation of inflammation by TGF-β

Yoshimura Akihiko, Wakabayashi Yu, Mori Tomoaki

Journal of Biochemistry 147 （ 6 ） 781 - 792 2010年06月

ISSN 0021-924X

Transforming growth factor-β (TGF-β) has been shown to play an essential role in the suppression of inflammation, yet recent studies have revealed the positive roles of TGF-β in inflammatory responses. For example, TGF-β induces Foxp3-positive regulatory T cells (iTregs) in the presence of interleukin-2 (IL-2), while in the presence of IL-6, it induces pathogenic IL-17 producing Th17 cells. TGF-β inhibits the proliferation of immune cells as well as cytokine production via Foxp3-dependent and -independent mechanisms. Little is known about molecular mechanisms involved in immune suppression via TGF-β; however, Smad2/3 have been shown to play essential roles in Foxp3 induction as well as in IL-2 and IFN-γ suppression, whereas Th17 differentiation is promoted via the Smad-independent pathway. Interaction between TGF-β and other cytokine signaling is important in establishing the balance of immunity and tolerance. © The Authors 2010. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

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Cellular and molecular basis for the regulation of inflammation by TGF-β

Yoshimura Akihiko, Wakabayashi Yu, Mori Tomoaki

Journal of Biochemistry 147 （ 6 ） 781 - 792 2010年06月

ISSN 0021-924X

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Interaction between Ebola virus glycoprotein and host Toll-like receptor 4 leads to induction of proinflammatory cytokines and SOCS1

Atsushi Okumura, Pitha Paula M., Yoshimura Akihiko, Harty Ronald N.

Journal of Virology 84 （ 1 ） 27 - 33 2010年01月

ISSN 0022-538X

Ebola virus initially targets monocytes and macrophages, which can lead to the release of proinflammatory cytokines and chemokines. These inflammatory cytokines are thought to contribute to the development of circulatory shock seen in fatal Ebola virus infections. Here we report that host Toll-like receptor 4 (TLR4) is a sensor for Ebola virus glycoprotein (GP) on virus-like particles (VLPs) and that resultant TLR4 signaling pathways lead to the production of proinflammatory cytokines and suppressor of cytokine signaling 1 (SOCS1) in a human monocytic cell line and in HEK293-TLR4/MD2 cells stably expressing the TLR4/MD2 complex. Ebola virus GP was found to interact with TLR4 by immunoprecipitation/Western blot analyses, and Ebola virus GP on VLPs was able to stimulate expression of NF-κB in a TLR4-dependent manner. Interestingly, we found that budding of Ebola virus VLPs was more pronounced in TLR4-stimulated cells than in unstimulated control cells. In sum, these findings identify the host innate immune protein TLR4 as a sensor for Ebola virus GP which may play an important role in the immunopathogenesis of Ebola virus infection. Copyright © 2010, American Society for Microbiology.

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Interaction between Ebola virus glycoprotein and host Toll-like receptor 4 leads to induction of proinflammatory cytokines and SOCS1

Atsushi Okumura, Pitha Paula M., Yoshimura Akihiko, Harty Ronald N.

Journal of Virology 84 （ 1 ） 27 - 33 2010年01月

ISSN 0022-538X

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Role of T lymphocytes in ischemic brain injury

Shichita Takashi, Konoeda Fumie, Yoshimura Akihiko

Clinical Neurology 50 （ 11 ） 878 - 880 2010年

ISSN 0009-918X

Recently, inflammation has been implicated in the progression of cerebral ischemic injury. Especially, T lymphocytes have been shown to infiltrate into the ischemic brain 24 hours after the onset, however, the function and specific subpopulation of these infiltrated T lymphocytes have not been fully understood. By using cytokine-deficient mice with transient focal ischemia model, we have shown that IL-23 and IL-17 but not IL-6 or IFN-γ play pivotal roles in the ischemic brain injury. We found that IL-23, which was mainly produced from infiltrated macrophages, induced IL-17-producing T lymphocytes in the ischemic brain. IL-23 and IL-17 expression increased 1 day or 3 day after ischemic injury, respectively, and promoted inflammatory responses by increasing the expression of neurotoxic factors. To our surprise, IL-17 was mainly produced by γδT lymphocytes, but not helper T cells. Based on these findings, we have tried to develop new therapeutic strategy for the progression of brain infarction. We found that administration of FTY720 (Fingolimod) and antibody against γδT lymphocytes attenuated ischemic brain damage. Furthermore, antibody against p40 which neutralizes both IL-23 and IL-12 simultaneously was also effective. Therefore, anti-cytokine therapy will be applicable for neuroprotection in the delayed phase of brain ischemia.

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TGF-β function in immune suppression

Yoshimura Akihiko, Muto Go

Current topics in microbiology and immunology 350 127 - 147 2010年

ISSN 0070-217X

Transforming growth factor-β (TGF-β) has been shown to play an essential role in establishing immunological tolerance, yet recent studies have revealed the pro-inflammatory roles of TGF-β in inflammatory responses. TGF-β induces Foxp3-positive regulatory T cells (iTregs), while in the presence of IL-6, it induces pathogenic IL-17 producing Th17 cells. TGF-β inhibits the proliferation of T cells as well as cytokine production via Foxp3-dependent and independent mechanisms. On the one hand, little is known about molecular mechanisms involved in immune suppression via TGF-β however, recent studies suggest that Smad2 as well as Smad3 play essential roles in Foxp3 induction and cytokine suppression, whereas Th17 differentiation is promoted via the Smad-independent pathway. Mutual suppression of signaling between TGF-β and inflammatory cytokines has been shown to be necessary for the balance of immunity and tolerance. © Springer-Verlag Berlin Heidelberg 2011.

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Role of T lymphocytes in ischemic brain injury

Shichita Takashi, Konoeda Fumie, Yoshimura Akihiko

Clinical Neurology 50 （ 11 ） 878 - 880 2010年

ISSN 0009-918X

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TGF-β function in immune suppression

Yoshimura Akihiko, Muto Go

Current topics in microbiology and immunology 350 127 - 147 2010年

ISSN 0070-217X

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Erratum

Yoshida Ryoko, Takaesu Giichi, Yoshida Hideyuki, Okamoto Fuyuki, Yoshioka Tomoko, Choi Yongwon, Akira Shizuo, Kawai Taro, Yoshimura Akihiko, Kobayashi Takashi

Journal of Biological Chemistry 284 （ 52 ） 36720 2009年12月

ISSN 0021-9258

Signal-transducing adaptor protein-2 regulates stromal cell-derived factor-1α-induced chemotaxis in T cells

Sekine Yuichi, Ikeda Osamu, Tsuji Satoshi, Yamamoto Chikako, Muromoto Ryuta, Nanbo Asuka, Oritani Kenji, Yoshimura Akihiko, Matsuda Tadashi

Journal of Immunology 183 （ 12 ） 7966 - 7974 2009年12月

ISSN 0022-1767

Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains pleckstrin and Src homology 2-like domains, as well as a YXXQ motif in its C-terminal region. Our previous studies revealed that STAP-2 regulates integrin-mediated T cell adhesion. In the present study, we find that STAP-2 expression affects Jurkat T cell migration after stromal cell-derived factor-1α (SDF-1α)-treatment. Furthermore, STAP-2-deficient T cells exhibit reduced cell migration after SDF-1α-treatment. Importantly, overexpression of STAP-2 in Jurkat T cells induces activation of small guanine triphosphatases, such as Rac1 and Cdc42. Regarding the mechanism for this effect, we found that STAP-2 associates with Vav1, the guanine-nucleotide exchanging factor for Rac1, and enhances downstream Vav1/Rac1 signaling. These results reveal a novel STAP-2-mediated mechanism for the regulation of SDF-1α-induced chemotaxis of T cells via activation of Vav1/Rac1 signaling. Copyright © 2009 by The American Association of Immunologists, Inc.

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SOCS3 in T and NKT cells negatively regulates cytokine production and ameliorates ConA-induced hepatitis

Nakaya Mako, Hashimoto Masayuki, Nakagawa Ryusuke, Wakabayashi Yu, Ishizaki Takuma, Takada Ichiro, Komai Kyoko, Yoshida Hiroki, Yoshimura Akihiko

Journal of Immunology 183 （ 11 ） 7047 - 7053 2009年12月

ISSN 0022-1767

Suppressor of cytokine signaling 3 (SOCS3), a negative-feedback molecule for cytokine signaling, has been implicated in protection against liver injury. Previous studies have shown that overexpression of SOCS3 in the liver by adenovirus or membrane permeable recombinant protein protected the liver from various injuries. However it remained uncertain in which type of cells SOCS3 suppresses liver injury. In this study, we demonstrated that forced expression of SOCS3 in T and NKT cells suppressed ConA-induced hepatitis using T and NKT cell-specific SOCS3 transgenic (Lck-SOCS3 Tg) mice. IFN-γ and IL-4 production was reduced in Lck-SOCS3 Tg mice as well as splenocytes treated with ConA. IFN-γ and IL-4 levels were also reduced in Lck-SOCS3 Tg mice administrated with α-galactosylceramide, suggesting that SOCS3 in NKT cells has suppressive function. Sustained expression of SOCS3 in an NKT cell line also resulted in reduced expression of various cytokines and transcription factors. In contrast, T and NKT cell-specific SOCS3 conditional knockout (Lck-SOCS3 cKO) mice were hypersensitive to ConA-mediated hepatitis. Isolated SOCS3-deficient NKT cells produced higher levels of IFN-γ and IL-4. These data indicate that SOCS3 plays a negative regulatory role in NKT cell activation and that forced expression of SOCS3 in NKT cells is effective in preventing hepatitis. Copyright © 2009 by The American Association of Immunologists, Inc.

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Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis

Taleb Soraya, Romain Mélissa, Ramkhelawon Bhama, Uyttenhove Catherine, Pasterkamp Gerard, Herbin Olivier, Esposito Bruno, Perez Nicolas, Yasukawa Hideo, Van Snick Jacques, Yoshimura Akihiko, Tedgui Alain, Mallat Ziad

Journal of Experimental Medicine 206 （ 10 ） 2067 - 2077 2009年09月

ISSN 0022-1007

Atherosclerosis is an inflammatory vascular disease responsible for the first cause of mortality worldwide. Recent studies have clearly highlighted the critical role of the immunoinflammatory balance in the modulation of disease development and progression. However, the immunoregulatory pathways that control atherosclerosis remain largely unknown. We show that loss of suppressor of cytokine signaling (SOCS) 3 in T cells increases both interleukin (IL)-17 and IL-10 production, induces an antiinflammatory macrophage phenotype, and leads to unexpected IL-17-dependent reduction in lesion development and vascular inflammation. In vivo administration of IL-17 reduces endothelial vascular cell adhesion molecule-1 expression and vascular T cell infiltration, and significantly limits atherosclerotic lesion development. In contrast, overexpression of SOCS3 in T cells reduces IL-17 and accelerates atherosclerosis. We also show that in human lesions, increased levels of signal transducer and activator of transcription (STAT) 3 phosphorylation and IL-17 are associated with a stable plaque phenotype. These results identify novel SOCS3-controlled IL-17 regulatory pathways in atherosclerosis and may have important implications for the understanding of the increased susceptibility to vascular inflammation in patients with dominant-negative STAT3 mutations and defective Th17 cell differentiation. © 2009 Taleb et al.

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Sprouty4 deficiency potentiates Ras-independent angiogenic signals and tumor growth

Taniguchi Koji, Ishizaki Takuma, Ayada Toranoshin, Sugiyama Yuki, Wakabayashi Yu, Sekiya Takashi, Nakagawa Ryusuke, Yoshimura Akihiko

Cancer Science 100 （ 9 ） 1648 - 1654 2009年09月

ISSN 1347-9032

Sprouty proteins have been shown to negatively regulate a variety of receptor tyrosine kinase (RTK) signaling pathways and are considered to be tumor suppressor proteins. The pathophysiological functions of Sproutys in vivo remain to be investigated. In this study, we examined the physiological function of Sprouty4 as an angiogenic regulator, using Sprouty4 knockout (KO) mice and cells.We found that transplanted tumor cells grow much faster in Sprouty4 KO mice than in wild type (WT) mice, which we associate with enhanced neovascularization in the tumors transplanted into Sprouty4 KO mice. Moreover, vascular endothelial growth factor (VEGF)-A-induced angiogenesis and vascular permeability in vivo were enhanced in Sprouty4 KO mice compared with WT mice. Ex vivo angiogenesis, which we induced by VEGF-A, basic fibroblast growth factor (bFGF), and sphingosine-1-phosphate (S1P), was also enhanced in the aortas of Sprouty4 KO mice. We demonstrated that Sprouty4 suppresses Ras-independent VEGF-A and S1P signaling,while it does not affect Ras-dependent VEGF-C signaling. These data indicate that Sprouty4 selectively suppresses Ras-independent angiogenic factor signals and is an important negative regulator of pathophysiological angiogenesis. © 2009 Japanese Cancer Association.

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Pivotal role of cerebral interleukin-17-producing T cells in the delayed phase of ischemic brain injury

Shichita Takashi, Sugiyama Yuki, Ooboshi Hiroaki, Sugimori Hiroshi, Nakagawa Ryusuke, Takada Ichiro, Iwaki Toru, Okada Yasunori, Iida Mitsuo, Cua Daniel J., Iwakura Yoichiro, Yoshimura Akihiko

Nature Medicine 15 （ 8 ） 946 - 950 2009年08月

ISSN 1078-8956

Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that T lymphocytes, but not CD4 ⁺ helper T cells, were a major source of IL-17. Moreover, depletion of T lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including T lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.

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吉村 昭彦

論文 - 吉村 昭彦

吉村　昭彦

論文 - 吉村　昭彦