Updated on 2025/12/06

All information, except for affiliations, is reprinted from the information registered on researchmap.

写真a

 
Hideyuki Yanai
 
Organization
Graduate School of Medicine Department of Medicine Cancer Biology Professor
School of Medicine Medical Course
Title
Professor
Homepage
http://mol-immu.umin.jp/
External link

Degree

  • 博士（医学） ( 東京大学 )

Research Interests

  • Innate Immunity, Inflammation, Infection, Cancer, Interferon

Research Areas

  • Life Science / Tumor biology

  • Life Science / Immunology

Education

  • 東京大学大学院   医学系研究科   病因・病理学専攻 博士課程

    2001.4 - 2005.3

    　 More details

  • Gakushuin University

    1999.4 - 2001.3

    　 More details

  • Gakushuin University   Faculty of Science   Department of Chemistry

    1995.4 - 1999.3

    　 More details

Research History

  • 横浜市立大学 医学部・医学研究科   教授

    2025.8

    　 More details

  • 東京大学先端科学技術研究センター   客員上級研究員

    2025.8

    　 More details

  • LSBM, RCAST   Project Associate Professor

    2019.4 - 2025.7

    　 More details

  • The University of Tokyo   Institute of Industrial Science

    2014.7 - 2019.3

    　 More details

  • The University of Tokyo   Institute of Industrial Science

    2012.4 - 2014.6

    　 More details

  • 東京大学大学院医学系研究科   助教

    2007.4 - 2012.3

    　 More details

  • 東京大学大学院医学系研究科   助手

    2006.4 - 2007.3

    　 More details

  • 東京大学医学系研究科   学術研究支援員

    2005.4 - 2006.3

    　 More details

▼display all

Professional Memberships

  • 日本がん分子標的治療学会

    2022.1

    　 More details

  • 日本Cell Death学会

    2021

    　 More details

  • International Cytokine and Interferon Society (ICIS)

    2018.4

    　 More details

  • THE MOLECULAR BIOLOGY SOCIETY OF JAPAN

    　 More details

  • THE JAPANESE SOCIETY OF INTERFERON & CYTOKINE RESEARCH

    　 More details

  • THE JAPANESE SOCIETY FOR IMMUNOLOGY

    　 More details

  • THE JAPANESE CANCER ASSOCIATION

    　 More details

▼display all

Committee Memberships

  • 日本癌学会   評議員  

    2025   

    　 More details

  • 日本免疫学会   評議員  

    2023   

    　 More details

  • 日本Cell Death学会   評議員  

    2022   

    　 More details

  • 第85回日本癌学会学術総会   プログラム委員  

       

    　 More details

  • 第84回日本癌学会学術総会   プログラム委員  

       

    　 More details

Papers

  • Inhibitory effect of streamer discharge on the local recurrence of B16F10 melanoma tumor in mice

    Ryuichiro Ito, Ryota Sumitomo, Misa Iizawa, Hideyuki Yanai, Ryo Ono

    JOURNAL OF PHYSICS D-APPLIED PHYSICS   58 ( 13 )   2025.3

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1088/1361-6463/ada98c

    Web of Science

    researchmap

  • Blood TCTP as a potential biomarker associated with immunosuppressive features and poor clinical outcomes in metastatic gastric cancer. International journal

    Hyung-Don Kim, Seyoung Jung, Yeong Hak Bang, Jiae Kim, Hee Jeong Kim, Hyung Eun Lee, Jaewon Hyung, Changhoon Yoo, Won-Tae Kim, Myeong-Jin Yoon, Hayoung Lee, Jeong-Hyun Ryou, Hyungsu Jeon, Hideyuki Yanai, Jeong Seok Lee, Gwanghee Lee, Min-Hee Ryu

    Journal for immunotherapy of cancer   13 ( 3 )   2025.3

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND: No established biomarker exists for specific myeloid cell populations or in gastric cancer. This study aimed to explore the prognostic and immunological relevance of plasma translationally controlled tumor protein (TCTP) in patients with advanced gastric cancer treated with an immune checkpoint inhibitor and/or cytotoxic chemotherapy. METHODS: Plasma samples were prospectively collected from the cohorts of patients with gastric cancer treated with first-line fluoropyrimidine plus platinum chemotherapy (n=143, cohort 1) and third-line nivolumab (n=165, cohort 2). Plasma TCTP levels were quantified using ELISA, and multiplex proteomic analysis (Olink) was conducted to assess expression levels of immune-related proteins. External single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics datasets were employed to validate the findings. RESULTS: Patients with high plasma TCTP levels (TCTP-high group) exhibited poor progression-free survival (PFS) and overall survival (OS) with first-line chemotherapy compared with those with low levels (TCTP-low group) in cohort 1 (HR: 1.73 for PFS; 1.77 for OS). In the TCTP-high group, proteins associated with immunosuppressive myeloid cells, angiogenesis, and immune exclusion of T/natural killer (NK) cell function were upregulated, whereas proteins involved in T-cell activation/exhaustion were significantly upregulated in the TCTP-low group. scRNA-seq analyses identified a myeloid subset with high TPT1 (encoding TCTP) expression and TCTP-related molecules, enriched with inhibitory myeloid inflammation gene signatures and providing inhibitory signals to T/NK cells (Macrophage-chemokine). Spatial transcriptomics analyses revealed a tumor-cell-enriched cluster co-localized with the Macrophage-chemokine subset, which exhibited the highest TPT1 expression and a positive correlation between its abundance and average TPT1 levels. In nivolumab-treated patients (cohort 2), the high TCTP group was associated with poor survival outcomes (HR: 1.39 for PFS; 1.47 for OS). CONCLUSIONS: Plasma TCTP is a prognostic biomarker, reflecting clinically relevant immunosuppressive myeloid signals in patients with gastric cancer.

    DOI： 10.1136/jitc-2024-010455

    PubMed

    researchmap

  • 自己指向性免疫学の新展開 : 生体防御における自己認識の功罪(Vol.21)腫瘍死細胞由来分子による免疫制御機構

    292 ( 3 )   241 - 246   2025.1

    　More details

  • Hypoxia activates SREBP2 through Golgi disassembly in bone marrow-derived monocytes for enhanced tumor growth. International journal

    Ryuichi Nakahara, Sho Aki, Maki Sugaya, Haruka Hirose, Miki Kato, Keisuke Maeda, Daichi M Sakamoto, Yasuhiro Kojima, Miyuki Nishida, Ritsuko Ando, Masashi Muramatsu, Melvin Pan, Rika Tsuchida, Yoshihiro Matsumura, Hideyuki Yanai, Hiroshi Takano, Ryoji Yao, Shinsuke Sando, Masabumi Shibuya, Juro Sakai, Tatsuhiko Kodama, Hiroyasu Kidoya, Teppei Shimamura, Tsuyoshi Osawa

    The EMBO journal   e114032   2023.10

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    Bone marrow-derived cells (BMDCs) infiltrate hypoxic tumors at a pre-angiogenic state and differentiate into mature macrophages, thereby inducing pro-tumorigenic immunity. A critical factor regulating this differentiation is activation of SREBP2-a well-known transcription factor participating in tumorigenesis progression-through unknown cellular mechanisms. Here, we show that hypoxia-induced Golgi disassembly and Golgi-ER fusion in monocytic myeloid cells result in nuclear translocation and activation of SREBP2 in a SCAP-independent manner. Notably, hypoxia-induced SREBP2 activation was only observed in an immature lineage of bone marrow-derived cells. Single-cell RNA-seq analysis revealed that SREBP2-mediated cholesterol biosynthesis was upregulated in HSCs and monocytes but not in macrophages in the hypoxic bone marrow niche. Moreover, inhibition of cholesterol biosynthesis impaired tumor growth through suppression of pro-tumorigenic immunity and angiogenesis. Thus, our findings indicate that Golgi-ER fusion regulates SREBP2-mediated metabolic alteration in lineage-specific BMDCs under hypoxia for tumor progression.

    DOI： 10.15252/embj.2023114032

    PubMed

    researchmap

  • Acidic extracellular pH drives accumulation of N1-acetylspermidine and recruitment of protumor neutrophils. International journal

    Miki Kato, Keisuke Maeda, Ryuichi Nakahara, Haruka Hirose, Ayano Kondo, Sho Aki, Maki Sugaya, Sana Hibino, Miyuki Nishida, Manami Hasegawa, Hinano Morita, Ritsuko Ando, Rika Tsuchida, Minoru Yoshida, Tatsuhiko Kodama, Hideyuki Yanai, Teppei Shimamura, Tsuyoshi Osawa

    PNAS nexus   2 ( 10 )   pgad306   2023.10

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    An acidic tumor microenvironment plays a critical role in tumor progression. However, understanding of metabolic reprogramming of tumors in response to acidic extracellular pH has remained elusive. Using comprehensive metabolomic analyses, we demonstrated that acidic extracellular pH (pH 6.8) leads to the accumulation of N1-acetylspermidine, a protumor metabolite, through up-regulation of the expression of spermidine/spermine acetyltransferase 1 (SAT1). Inhibition of SAT1 expression suppressed the accumulation of intra- and extracellular N1-acetylspermidine at acidic pH. Conversely, overexpression of SAT1 increased intra- and extracellular N1-acetylspermidine levels, supporting the proposal that SAT1 is responsible for accumulation of N1-acetylspermidine. While inhibition of SAT1 expression only had a minor effect on cancer cell growth in vitro, SAT1 knockdown significantly decreased tumor growth in vivo, supporting a contribution of the SAT1-N1-acetylspermidine axis to protumor immunity. Immune cell profiling revealed that inhibition of SAT1 expression decreased neutrophil recruitment to the tumor, resulting in impaired angiogenesis and tumor growth. We showed that antineutrophil-neutralizing antibodies suppressed growth in control tumors to a similar extent to that seen in SAT1 knockdown tumors in vivo. Further, a SAT1 signature was found to be correlated with poor patient prognosis. Our findings demonstrate that extracellular acidity stimulates recruitment of protumor neutrophils via the SAT1-N1-acetylspermidine axis, which may represent a metabolic target for antitumor immune therapy.

    DOI： 10.1093/pnasnexus/pgad306

    PubMed

    researchmap

  • Tumor cell-derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8+ T cell activation. International journal

    Sana Hibino, Shotaro Eto, Sho Hangai, Keiko Endo, Sanae Ashitani, Maki Sugaya, Tsuyoshi Osawa, Tomoyoshi Soga, Tadatsugu Taniguchi, Hideyuki Yanai

    Proceedings of the National Academy of Sciences of the United States of America   120 ( 24 )   e2305245120   2023.6

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    The activation and expansion of T cells that recognize cancer cells is an essential aspect to antitumor immunity. Tumors may escape destruction by the immune system through ectopic expression of inhibitory immune ligands typically exemplified by the PD-L1/PD-1 pathway. Here, we reveal another facet of tumor evasion from T cell surveillance. By secretome profiling of necrotic tumor cells, we identified an oncometabolite spermidine as a unique inhibitor of T cell receptor (TCR) signaling. Mechanistically, spermidine causes the downregulation of the plasma membrane cholesterol levels, resulting in the suppression of TCR clustering. Using syngeneic mouse models, we show that spermidine is abundantly detected in the tumor immune microenvironment (TIME) and that administration of the polyamine synthesis inhibitor effectively enhanced CD8+ T cell-dependent antitumor responses. Further, the combination of the polyamine synthesis inhibitor with anti-PD-1 immune checkpoint antibody resulted in a much stronger antitumor immune response. This study reveals an aspect of immunosuppressive TIME, wherein spermidine functions as a metabolic T cell checkpoint that may offer a unique approach for promoting tumor immunotherapy.

    DOI： 10.1073/pnas.2305245120

    PubMed

    researchmap

  • Potential of <scp>HMGB</scp> ‐inhibitory oligodeoxynucleotide <scp>ISM ODN</scp> to neutrophil recruitment in mouse model of hepatitis International journal

    Asuka Inoue, Shiho Chiba, Shotaro Eto, Tadatsugu Taniguchi, Hideyuki Yanai

    Genes to Cells   28 ( 3 )   202 - 210   2022.12

    　More details

    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    High-mobility group box 1 (HMGB1) is a nucleotide-binding chromatin protein that has also been characterized as a prototypical damage-associate molecular pattern. It triggers inflammatory responses upon release from damaged or dying cells. In fact, HMGB1 has been linked to the induction of many inflammatory diseases through immune cell activation including neutrophil recruitment. In this study, we examined the impact of HMGB1-binding inhibitory oligodeoxynucleotide (ISM ODN) on the development of hepatitis using a murine model of the disease. Our results indicate that ISM ODN effectively suppresses pathological features of hepatitis, including neutrophil accumulation. This study therefore may offer clinical insight into the treatment of hepatitis and possibly other inflammatory diseases.

    DOI： 10.1111/gtc.13002

    PubMed

    researchmap

  • Erratum: Antitumor abscopal effects in mice induced by normal tissue irradiation using pulsed streamer discharge plasma (Journal of Physics D: Applied Physics (2022) 55 (17LT01) DOI: 10.1088/1361-6463/ac4c23)

    Reima Jinno, Atsushi Komuro, Hideyuki Yanai, Ryo Ono

    Journal of Physics D: Applied Physics   55 ( 29 )   2022.7

    　More details

    Publishing type：Research paper (scientific journal)  

    DOI： 10.1088/1361-6463/ac6a24

    Scopus

    researchmap

  • Antitumor abscopal effects in mice induced by normal tissue irradiation using pulsed streamer discharge plasma

    Reima Jinno, Atsushi Komuro, Hideyuki Yanai, Ryo Ono

    Journal of Physics D: Applied Physics   55 ( 17 )   17LT01 - 17LT01   2022.4

    　More details

    Publishing type：Research paper (scientific journal)   Publisher：IOP Publishing  

    Abstract

    An antitumor abscopal effect is occasionally observed in radiotherapy and plasma treatment. It is a remote antitumor effect induced by tumor irradiation that delays the growth of other distant, nonirradiated tumors. In this study, it was demonstrated that the plasma irradiation of normal tissues (not tumors) also leads to an abscopal effect. When a pulsed streamer discharge was irradiated to the left flanks of mice where no tumor existed, the growth of murine colorectal carcinoma CT26 tumors in their right limbs was delayed. This abscopal effect was significant for mice with small tumors before plasma irradiation, whereas it was not significant for those with large tumors before plasma irradiation. The abscopal effect induced by normal tissue irradiation was compared to the antitumor effect induced by direct tumor irradiation. Contrary to our expectation, normal tissue irradiation delayed the tumor growth equally or more than the direct tumor irradiation under the present experimental conditions.

    DOI： 10.1088/1361-6463/ac4c23

    researchmap

    Other Link： https://iopscience.iop.org/article/10.1088/1361-6463/ac4c23/pdf

  • Therapeutic effects of genetic and chemical targeting of IRF5 on experimental SLE(和訳中)

    Ban Tatsuma, Kikuchi Masako, Sato Go, Manabe Akio, Nishiyama Akira, Yoshimi Ryusuke, Yanai Hideyuki, Yamamoto Tadashi, Taniguchi Tadatsugu, Ito Shuichi, Tamura Tomohiko

    日本免疫学会総会・学術集会記録   50 ( Proceedings )   3 - O/P   2021.11

    　More details

    Language：English   Publisher：(NPO)日本免疫学会  

    researchmap

  • Identification and characterization of a novel Enterococcus bacteriophage with potential to ameliorate murine colitis. International journal

    Junko Nishio, Hideo Negishi, Mika Yasui-Kato, Shoji Miki, Kazuhiko Miyanaga, Kotaro Aoki, Takuma Mizusawa, Masami Ueno, Akira Ainai, Masafumi Muratani, Sho Hangai, Hideyuki Yanai, Hideki Hasegawa, Yoshikazu Ishii, Yasunori Tanji, Tadatsugu Taniguchi

    Scientific reports   11 ( 1 )   20231 - 20231   2021.10

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    Increase of the enteric bacteriophages (phage), components of the enteric virome, has been associated with the development of inflammatory bowel diseases. However, little is known about how a given phage contributes to the regulation of intestinal inflammation. In this study, we isolated a new phage associated with Enterococcus gallinarum, named phiEG37k, the level of which was increased in C57BL/6 mice with colitis development. We found that, irrespective of the state of inflammation, over 95% of the E. gallinarum population in the mice contained phiEG37k prophage within their genome and the phiEG37k titers were proportional to that of E. gallinarum in the gut. To explore whether phiEG37k impacts intestinal homeostasis and/or inflammation, we generated mice colonized either with E. gallinarum with or without the prophage phiEG37k. We found that the mice colonized with the bacteria with phiEG37k produced more Mucin 2 (MUC2) that serves to protect the intestinal epithelium, as compared to those colonized with the phage-free bacteria. Consistently, the former mice were less sensitive to experimental colitis than the latter mice. These results suggest that the newly isolated phage has the potential to protect the host by strengthening mucosal integrity. Our study may have clinical implication in further understanding of how bacteriophages contribute to the gut homeostasis and pathogenesis.

    DOI： 10.1038/s41598-021-99602-4

    PubMed

    researchmap

  • Irf5 siRNA-loaded biodegradable lipid nanoparticles ameliorate concanavalin A-induced liver injury

    Wataru Kawase, Daisuke Kurotaki, Yuta Suzuki, Hiroshi Ishihara, Tatsuma Ban, Go R. Sato, Juri Ichikawa, Hideyuki Yanai, Tadatsugu Taniguchi, Kappei Tsukahara, Tomohiko Tamura

    Molecular Therapy - Nucleic Acids   25   708 - 715   2021.9

    　More details

    Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.omtn.2021.08.023

    researchmap

  • Damage-associated molecular patterns and Toll-like receptors in the tumor immune microenvironment. International journal

    Hideyuki Yanai, Sho Hangai, Tadatsugu Taniguchi

    International immunology   2021.8

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    As clinically demonstrated by the success of immunotherapies to improve survival outcomes, tumors are known to gain a survival advantage by circumventing immune surveillance. A defining feature of this is the creation and maintenance of a tumor immune microenvironment (TIME) that directly and indirectly alters the host's immunologic signaling pathways through a variety of mechanisms. Tumor-intrinsic mechanisms that instruct the formation and maintenance of the TIME have been an area of intensive study, such as the identification and characterization of soluble factors actively and passively released by tumor cells that modulate immune cell function. In particular, damage-associated molecular pattern molecules (DAMPs) typically released by necrotic tumor cells are recognized by innate immune receptors such as Toll-like receptors (TLRs) and stimulate immune cells within TIME. Given their broad and potent effects on the immune system, a better understanding for how DAMP and TLR interactions sculpt the TIME to favor tumor growth would identify new strategies and approaches for cancer immunotherapy.

    DOI： 10.1093/intimm/dxab050

    PubMed

    researchmap

  • Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease. International journal

    Tatsuma Ban, Masako Kikuchi, Go R Sato, Akio Manabe, Noriko Tagata, Kayo Harita, Akira Nishiyama, Kenichi Nishimura, Ryusuke Yoshimi, Yohei Kirino, Hideyuki Yanai, Yoshiko Matsumoto, Shuichi Suzuki, Hiroe Hihara, Masashi Ito, Kappei Tsukahara, Kentaro Yoshimatsu, Tadashi Yamamoto, Tadatsugu Taniguchi, Hideaki Nakajima, Shuichi Ito, Tomohiko Tamura

    Nature communications   12 ( 1 )   4379 - 4379   2021.7

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional Irf5 deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors.

    DOI： 10.1038/s41467-021-24609-4

    PubMed

    researchmap

  • Orchestration of myeloid-derived suppressor cells in the tumor microenvironment by ubiquitous cellular protein TCTP released by tumor cells. International journal

    Sho Hangai, Takeshi Kawamura, Yoshitaka Kimura, Ching-Yun Chang, Sana Hibino, Daisuke Yamamoto, Yousuke Nakai, Ryosuke Tateishi, Masanobu Oshima, Hiroko Oshima, Tatsuhiko Kodama, Kyoji Moriya, Kazuhiko Koike, Hideyuki Yanai, Tadatsugu Taniguchi

    Nature immunology   22 ( 8 )   947 - 957   2021.7

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    One of most challenging issues in tumor immunology is a better understanding of the dynamics in the accumulation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TIME), as this would lead to the development of new cancer therapeutics. Here, we show that translationally controlled tumor protein (TCTP) released by dying tumor cells is an immunomodulator crucial to full-blown MDSC accumulation in the TIME. We provide evidence that extracellular TCTP mediates recruitment of the polymorphonuclear MDSC (PMN-MDSC) population in the TIME via activation of Toll-like receptor-2. As further proof of principle, we show that inhibition of TCTP suppresses PMN-MDSC accumulation and tumor growth. In human cancers, we find an elevation of TCTP and an inverse correlation of TCTP gene dosage with antitumor immune signatures and clinical prognosis. This study reveals the hitherto poorly understood mechanism of the MDSC dynamics in the TIME, offering a new rationale for cancer immunotherapy.

    DOI： 10.1038/s41590-021-00967-5

    PubMed

    researchmap

  • The impact of damage-associated molecules released from canine tumor cells on gene expression in macrophages. International journal

    Shotaro Eto, Hideyuki Yanai, Sho Hangai, Daiki Kato, Ryohei Nishimura, Takayuki Nakagawa

    Scientific reports   11 ( 1 )   8525 - 8525   2021.4

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    Dying or damaged cells that are not completely eradicated by the immune system release their intracellular components in the extracellular space. Aberrant exposure of the damage-associated molecules to the immune system is often associated with inflammation and cancer pathogenesis. Thus, elucidating the role of damage-associated molecules in inducing sterile immune responses is crucial. In this study, we show that prostaglandin E2 (PGE2) is produced in the supernatants from several types of canine necrotic tumor cell lines. Inhibition of PGE2 production by indomethacin, a potent inhibitor of cyclooxygenase (COX) enzymes, induces the expression of tumor necrosis factor (Tnf) mRNA in the necrotic tumor cell supernatants. These results comply with the previous observations reported in mouse cell lines. Furthermore, comprehensive ribonucleic acid-sequencing (RNA-seq) analysis revealed that three categories of genes were induced by the damage-associated molecules: (i) a group of PGE2-inducible genes, (ii) genes that promote inflammation and are suppressed by PGE2, and (iii) a group of genes not suppressed by PGE2. Collectively, our findings reveal the hitherto unknown immune regulatory system by PGE2 and damage-associated molecules, which may have clinical implications in inflammation and cancer.

    DOI： 10.1038/s41598-021-87979-1

    PubMed

    researchmap

  • Signal-transducing innate receptors in tumor immunity. International journal

    Sho Hangai, Yoshitaka Kimura, Tadatsugu Taniguchi, Hideyuki Yanai

    Cancer science   2021.2

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    The signal-transducing innate receptors represent classes of pattern recognition receptors (PRRs) that play crucial roles in the first line of the host defense against infections by the recognition of pathogen-derived molecules. Because of their poorly discriminative nature compared with antigen receptors of the adaptive immune system, they also recognize endogenous molecules and evoke immune responses without infection, resulting in the regulation of tumor immunity. Therefore, PRRs may be promising targets for effective cancer immunotherapy, either by activating or inhibiting them. Here, we summarize our current knowledge of signal-transducing PRRs in the regulation of tumor immunity.

    DOI： 10.1111/cas.14848

    PubMed

    researchmap

  • HMGB1-mediated chromatin remodeling attenuates Il24 gene expression for the protection from allergic contact dermatitis. International journal

    Naoyuki Senda, Hideyuki Yanai, Sana Hibino, Lei Li, Yu Mizushima, Tomomitsu Miyagaki, Mai Saeki, Yusuke Kishi, Sho Hangai, Junko Nishio, Makoto Sugaya, Tadatsugu Taniguchi, Shinichi Sato

    Proceedings of the National Academy of Sciences of the United States of America   118 ( 1 )   2021.1

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    Dysregulation of inflammatory cytokines in keratinocytes promote the pathogenesis of the skin inflammation, such as allergic contact dermatitis (ACD). High-mobility group box 1 protein (HMGB1) has been implicated in the promotion of skin inflammation upon its extracellular release as a damage-associated molecular pattern molecule. However, whether and how HMGB1 in keratinocytes contributes to ACD and other skin disorders remain elusive. In this study, we generated conditional knockout mice in which the Hmgb1 gene is specifically deleted in keratinocytes, and examined its role in ACD models. Interestingly, the mutant mice showed exacerbated skin inflammation, accompanied by increased ear thickening in 2,4-dinitrofluorobenezene-induced ACDs. The mRNA expression of interleukin-24 (IL-24), a cytokine known to critically contribute to ACD pathogenesis, was elevated in skin lesions of the mutant mice. As with constitutively expressed, IL-4-induced Il24 mRNA, expression was also augmented in the Hmgb1-deficient keratinocytes, which would account for the exacerbation of ACD in the mutant mice. Mechanistically, we observed an increased binding of trimethyl histone H3 (lys4) (H3K4me3), a hallmark of transcriptionally active genes, to the promoter region of the Il24 gene in the hmgb1-deficient cells. Thus, the nuclear HMGB1 is a critical "gate keeper" in that the dermal homeostasis is contingent to its function in chromatin remodeling. Our study revealed a facet of nuclear HMGB1, namely its antiinflammatory function in keratinocytes for the skin homeostasis.

    DOI： 10.1073/pnas.2022343118

    PubMed

    researchmap

  • Identification of U11snRNA as an endogenous agonist of TLR7-mediated immune pathogenesis. Reviewed International journal

    Hideo Negishi, Nobuyasu Endo, Yuki Nakajima, Tatsuaki Nishiyama, Yuichiro Tabunoki, Junko Nishio, Ryuji Koshiba, Atsushi Matsuda, Kosuke Matsuki, Tomohisa Okamura, Takako Negishi-Koga, Takeshi Ichinohe, Shunji Takemura, Hiroyuki Ishiwata, Shun-Ichiro Iemura, Tohru Natsume, Takaya Abe, Hiroshi Kiyonari, Takeshi Doi, Sho Hangai, Hideyuki Yanai, Keishi Fujio, Kazuhiko Yamamoto, Tadatsugu Taniguchi

    Proceedings of the National Academy of Sciences of the United States of America   116 ( 47 )   23653 - 23661   2019.11

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    The activation of innate immune receptors by pathogen-associated molecular patterns (PAMPs) is central to host defense against infections. On the other hand, these receptors are also activated by immunogenic damage-associated molecular patterns (DAMPs), typically released from dying cells, and the activation can evoke chronic inflammatory or autoimmune disorders. One of the best known receptors involved in the immune pathogenesis is Toll-like receptor 7 (TLR7), which recognizes RNA with single-stranded structure. However, the causative DAMP RNA(s) in the pathogenesis has yet to be identified. Here, we first developed a chemical compound, termed KN69, that suppresses autoimmunity in several established mouse models. A subsequent search for KN69-binding partners led to the identification of U11 small nuclear RNA (U11snRNA) as a candidate DAMP RNA involved in TLR7-induced autoimmunity. We then showed that U11snRNA robustly activated the TLR7 pathway in vitro and induced arthritis disease in vivo. We also found a correlation between high serum level of U11snRNA and autoimmune diseases in human subjects and established mouse models. Finally, by revealing the structural basis for U11snRNA's ability to activate TLR7, we developed more potent TLR7 agonists and TLR7 antagonists, which may offer new therapeutic approaches for autoimmunity or other immune-driven diseases. Thus, our study has revealed a hitherto unknown immune function of U11snRNA, providing insight into TLR7-mediated autoimmunity and its potential for further therapeutic applications.

    DOI： 10.1073/pnas.1915326116

    PubMed

    researchmap

  • 全身性自己免疫疾患 次の段階のSLE治療のためのI型interferonを越えた強力な標的としてのIRF5(Systemic autoimmune diseases-3 IRF5 as a potent target beyond type I interferons for the next stage SLE therapy)

    Kikuchi Masako, Ban Tatsuma, Sato Go R., Manabe Akio, Yoshimi Ryusuke, Yanai Hideyuki, Taniguchi Tadatsugu, Ito Shuichi, Tamura Tomohiko

    日本免疫学会総会・学術集会記録   47 ( Proceedings )   2 - O/P   2018.12

    　More details

    Language：English   Publisher：(NPO)日本免疫学会  

    researchmap

  • Cancer cell-derived HMGB1 promotes tumor growth by recruiting myeloid cells into the tumor microenvironment

    Hideyuki Yanai, Sho Hangai, Tadatsugu Taniguchi

    CANCER SCIENCE   109   1067 - 1067   2018.12

    　More details

    Language：English  

    Web of Science

    researchmap

  • Novel chemical compound SINCRO with dual function in STING-type I interferon and tumor cell death pathways Reviewed

    Kimura Y, Negishi H, Matsuda A, Endo N, Hangai S, Inoue A, Nishio J, Taniguchi T, Yanai H

    Cancer Science   109 ( 9 )   2687 - 2696   2018.9

    　More details

    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    DOI： 10.1111/cas.13726

    researchmap

    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.13726

  • Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice Reviewed

    Hideyuki Yanai, Shiho Chiba, Sho Hangai, Kohei Kometani, Asuka Inoue, Yoshitaka Kimura, Takaya Abe, Hiroshi Kiyonari, Junko Nishio, Naoko Taguchi-Atarashi, Yu Mizushima, Hideo Negishi, Rudolf Grosschedl, Tadatsugu Taniguchi

    Proceedings of the National Academy of Sciences of the United States of America   115 ( 20 )   5253 - 5258   2018.5

    　More details

    Language：English   Publishing type：Research paper (scientific journal)   Publisher：National Academy of Sciences  

    DOI： 10.1073/pnas.1803936115

    Scopus

    researchmap

  • Role of HMGB1 in tumor progression

    Hideyuki Yanai, Yoshitaka Kimura, Tadatsugu Taniguchi

    CANCER SCIENCE   109   73 - 73   2018.1

    　More details

    Language：English  

    Web of Science

    researchmap

  • Fine-tuning type I IFN signaling: A new chapter in the IFN saga Invited Reviewed

    Hideyuki Yanai, Tadatsugu Taniguchi

    CELL RESEARCH   27 ( 12 )   1407 - 1408   2017.12

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/cr.2017.118

    Web of Science

    researchmap

  • Gallbladder-derived surfactant protein D regulates gut commensal bacteria for maintaining intestinal homeostasis Reviewed

    Hana Sarashina-Kida, Hideo Negishi, Junko Nishio, Wataru Suda, Yuki Nakajima, Mika Yasui-Kato, Keiko Iwaisako, Sujin Kang, Nobuyasu Endo, Hideyuki Yanai, Masataka Asagiri, Hiroshi Kida, Masahira Hattori, Atsushi Kumanogoh, Tadatsugu Taniguchi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   114 ( 38 )   10178 - 10183   2017.9

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.1712837114

    Web of Science

    researchmap

  • The Interferon (IFN) Class of Cytokines and the IFN Regulatory Factor (IRF) Transcription Factor Family Invited Reviewed

    Negishi H, Taniguchi T, Yanai H

    Cold Spring Harb. Perspect. Biol.   2017.9

    　More details

    Language：English   Publishing type：Research paper (conference, symposium, etc.)  

    researchmap

  • The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response (vol 10, pg 481, 2017) Reviewed

    T. Okazaki, M. Higuchi, K. Takeda, K. Iwatsuki-Horimoto, M. Kiso, M. Miyagishi, H. Yanai, A. Kato, M. Yoneyama, T. Fujita, T. Taniguchi, Y. Kawaoka, H. Ichijo, Y. Gotoh

    SCIENCE SIGNALING   10 ( 481 )   2017.5

    　More details

  • Novel pegylated interferon-β as strong suppressor of the malignant ascites in a peritoneal metastasis model of human cancer Reviewed

    Tomokatsu Iwamura, Hideki Narumi, Tomohiko Suzuki, Hideyuki Yanai, Katsuyuki Mori, Koji Yamashita, Yoshiaki Tsushima, Tomomi Asano, Akiko Izawa, Shinobu Momen, Kazumi Nishimura, Hiromi Tsuchiyama, Masashi Uchida, Yuji Yamashita, Kiyoshi Okano, Tadatsugu Taniguchi

    Cancer Science   108 ( 4 )   581 - 589   2017.4

    　More details

    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

    DOI： 10.1111/cas.13176

    Scopus

    PubMed

    researchmap

  • Novel pegylated interferon- as strong suppressor of the malignant ascites in a peritoneal metastasis model of human cancer Reviewed

    Tomokatsu Iwamura, Hideki Narumi, Tomohiko Suzuki, Hideyuki Yanai, Katsuyuki Mori, Koji Yamashita, Yoshiaki Tsushima, Tomomi Asano, Akiko Izawa, Shinobu Momen, Kazumi Nishimura, Hiromi Tsuchiyama, Masashi Uchida, Yuji Yamashita, Kiyoshi Okano, Tadatsugu Taniguchi

    CANCER SCIENCE   108 ( 4 )   581 - 589   2017.4

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/cas.13176

    Web of Science

    researchmap

  • The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis Reviewed

    Yoshitaka Kimura, Asuka Inoue, Sho Hangai, Shinobu Saijo, Hideo Negishi, Junko Nishio, Sho Yamasaki, Yoichiro Iwakura, Hideyuki Yanai, Tadatsugu Taniguchi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   113 ( 49 )   14097 - 14102   2016.12

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.1617903113

    Web of Science

    researchmap

  • Lyn Kinase Suppresses the Transcriptional Activity of IRF5 in the TLR-MyD88 Pathway to Restrain the Development of Autoimmunity Reviewed

    Tatsuma Ban, Go R. Sato, Akira Nishiyama, Ai Akiyama, Marie Takasuna, Marina Umehara, Shinsuke Suzuki, Motohide Ichino, Satoko Matsunaga, Ayuko Kimura, Yayoi Kimura, Hideyuki Yanai, Sadakazu Miyashita, Junro Kuromitsu, Kappei Tsukahara, Kentaro Yoshimatsu, Itaru Endo, Tadashi Yamamoto, Hisashi Hirano, Akihide Ryo, Tadatsugu Taniguchi, Tomohiko Tamura

    IMMUNITY   45 ( 2 )   319 - 332   2016.8

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.immuni.2016.07.015

    Web of Science

    researchmap

  • A critical link between Lyn-mediated suppression of the TLR-MyD88-IRF5 pathway and the development of SLE-like disease Reviewed

    Ban Tatsuma, Sato Go, Nishiyama Akira, Al Akiyama, Takasuna Marie, Umehara Marina, Suzuki Shinsuke, Ichino Motohide, Matsunaga Satoko, Kimura Ayuko, Kimura Yayoi, Yanai Hideyuki, Miyashita Sadakazu, Kuromitsu Junro, Tsukahara Kappei, Yoshimatsu Kentaro, Endo Itaru, Yamamoto Tadashi, Hirano Hisashi, Ryo Akihide, Taniguchi Tadatsugu, Tamura Tomohiko

    JOURNAL OF IMMUNOLOGY   196   2016.5

    　More details

  • PGE2 induced in and released by dying cells functions as an inhibitory DAMP Reviewed

    Sho Hangai, Tomoka Ao, Yoshitaka Kimura, Kosuke Matsuki, Takeshi Kawamura, Hideo Negishi, Junko Nishio, Tatsuhiko Kodama, Tadatsugu Taniguchi, Hideyuki Yanai

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   113 ( 14 )   3844 - 3849   2016.4

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.1602023113

    Web of Science

    researchmap

  • Requirement of full TCR repertoire for regulatory T cells to maintain intestinal homeostasis Reviewed

    Junko Nishio, Minato Baba, Koji Atarashi, Takeshi Tanoue, Hideo Negishi, Hideyuki Yanai, Sonoko Habu, Shohei Hori, Kenya Honda, Tadatsugu Taniguchi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   112 ( 41 )   12770 - 12775   2015.10

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.1516617112

    Web of Science

    researchmap

  • The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response Reviewed

    Tomohiko Okazaki, Maiko Higuchi, Kohsuke Takeda, Kiyoko Iwatsuki-Horimoto, Maki Kiso, Makoto Miyagishi, Hideyuki Yanai, Atsushi Kato, Mitsutoshi Yoneyama, Takashi Fujita, Tadatsugu Taniguchi, Yoshihiro Kawaoka, Hidenori Ichijo, Yukiko Gotoh

    SCIENCE SIGNALING   8 ( 388 )   ra78   2015.8

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1126/scisignal.aab1883

    Web of Science

    researchmap

  • Innate immune receptor signaling and IRF family of transcription factors: Good deeds and misdeeds in oncogenesis Reviewed

    Hiroaki Ikushima, Hideyuki Yanai, Tadatsugu Taniguchi

    Inflammation and Immunity in Cancer   85 - 101   2015.1

    　More details

    Language：English   Publishing type：Part of collection (book)   Publisher：Springer Japan  

    DOI： 10.1007/978-4-431-55327-4_7

    Scopus

    researchmap

  • Nucleic acid sensing and beyond: virtues and vices of high-mobility group box 1 Invited Reviewed

    H. Yanai, T. Taniguchi

    JOURNAL OF INTERNAL MEDICINE   276 ( 5 )   444 - 453   2014.11

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/joim.12285

    Web of Science

    researchmap

  • Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses Reviewed

    Shiho Chiba, Hiroaki Ikushima, Hiroshi Ueki, Hideyuki Yanai, Yoshitaka Kimura, Sho Hangai, Junko Nishio, Hideo Negishi, Tomohiko Tamura, Shinobu Saijo, Yoichiro Iwakura, Tadatsugu Taniguchi

    ELIFE   3 ( 3 )   e04177   2014.8

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.7554/eLife.04177

    Web of Science

    researchmap

  • Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection Reviewed

    Hideyuki Yanai, Atsushi Matsuda, Jianbo An, Ryuji Koshiba, Junko Nishio, Hideo Negishi, Hiroaki Ikushima, Takashi Onoe, Hideki Ohdan, Nobuaki Yoshida, Tadatsugu Taniguchi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   110 ( 51 )   20699 - 20704   2013.12

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.1320808110

    Web of Science

    researchmap

  • Beneficial innate signaling interference for antibacterial responses by a Toll-like receptor-mediated enhancement of the MKP-IRF3 axis Reviewed

    Hideo Negishi, Kosuke Matsuki, Nobuyasu Endo, Hana Sarashina, Shoji Miki, Atsushi Matsuda, Keiko Fukazawa, Naoko Taguchi-Atarashi, Hiroaki Ikushima, Hideyuki Yanai, Junko Nishio, Kenya Honda, Yoichiro Fujioka, Yusuke Ohba, Tetsuo Noda, Shun'ichiro Taniguchi, Eisuke Nishida, Yongliang Zhang, Hongbo Chi, Richard A. Flavell, Tadatsugu Taniguchi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   110 ( 49 )   19884 - 19889   2013.12

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.1320145110

    Web of Science

    researchmap

  • Regulation of cooperative function of the Il12b enhancer and promoter by the interferon regulatory factors 3 and 5 Reviewed

    Ryuji Koshiba, Hideyuki Yanai, Atsushi Matsuda, Ayana Goto, Akira Nakajima, Hideo Negishi, Junko Nishio, Stephen T. Smale, Tadatsugu Taniguchi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   430 ( 1 )   95 - 100   2013.1

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.bbrc.2012.11.006

    Web of Science

    researchmap

  • High-mobility group box family of proteins: ligand and sensor for innate immunity Invited Reviewed

    Hideyuki Yanai, Tatsuma Ban, Tadatsugu Taniguchi

    TRENDS IN IMMUNOLOGY   33 ( 12 )   633 - 640   2012.12

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.it.2012.10.005

    Web of Science

    researchmap

  • Essential contribution of IRF3 to intestinal homeostasis and microbiota-mediated Tslp gene induction Reviewed

    Hideo Negishi, Shoji Miki, Hana Sarashina, Naoko Taguchi-Atarashi, Akira Nakajima, Kosuke Matsuki, Nobuyasu Endo, Hideyuki Yanai, Junko Nishio, Kenya Honda, Tadatsugu Taniguchi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   109 ( 51 )   21016 - 21021   2012.12

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.1219482110

    Web of Science

    researchmap

  • The IRF family of transcription factors Inception, impact and implications in oncogenesis Invited Reviewed

    Hideyuki Yanai, Hideo Negishi, Tadatsugu Taniguchi

    ONCOIMMUNOLOGY   1 ( 8 )   1376 - 1386   2012.11

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.4161/onci.22475

    Web of Science

    researchmap

  • Cross-interference of RLR and TLR signaling pathways modulates antibacterial T cell responses Reviewed

    Hideo Negishi, Hideyuki Yanai, Akira Nakajima, Ryuji Koshiba, Koji Atarashi, Atsushi Matsuda, Kosuke Matsuki, Shoji Miki, Takahiro Doi, Alan Aderem, Junko Nishio, Stephen T. Smale, Kenya Honda, Tadatsugu Taniguchi

    NATURE IMMUNOLOGY   13 ( 7 )   659 - +   2012.7

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/ni.2307

    Web of Science

    researchmap

  • Essential role of high-mobility group box proteins in nucleic acid-mediated innate immune responses Invited Reviewed

    H. Yanai, T. Ban, T. Taniguchi

    JOURNAL OF INTERNAL MEDICINE   270 ( 4 )   301 - 308   2011.10

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/j.1365-2796.2011.02433.x

    Web of Science

    researchmap

  • Suppression of immune responses by nonimmunogenic oligodeoxynucleotides with high affinity for high-mobility group box proteins (HMGBs) Reviewed

    Hideyuki Yanai, Shiho Chiba, Tatsuma Ban, Yukana Nakaima, Takashi Onoe, Kenya Honda, Hideki Ohdan, Tadatsugu Taniguchi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   108 ( 28 )   11542 - 11547   2011.7

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.1108535108

    Web of Science

    researchmap

  • Generation of mice deficient in RNA-binding motif protein 3 (RBM3) and characterization of its role in innate immune responses and cell growth Reviewed

    Atsushi Matsuda, Masahiro Ogawa, Hideyuki Yanai, Daiji Naka, Ayana Goto, Tomoka Ao, Yuji Tanno, Kiyoshi Takeda, Yoshinori Watanabe, Kenya Honda, Tadatsugu Taniguchi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   411 ( 1 )   7 - 13   2011.7

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.bbrc.2011.06.038

    Web of Science

    researchmap

  • IRF3 regulates cardiac fibrosis but not hypertrophy in mice during angiotensin II-induced hypertension Reviewed

    Kensuke Tsushima, Tomoko Osawa, Hideyuki Yanai, Akira Nakajima, Akinori Takaoka, Ichiro Manabe, Yusuke Ohba, Yasushi Imai, Tadatsugu Taniguchi, Ryozo Nagai

    FASEB JOURNAL   25 ( 5 )   1531 - 1543   2011.5

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1096/fj.10-174615

    Web of Science

    researchmap

  • Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus Reviewed

    David A. Savitsky, Hideyuki Yanai, Tomohiko Tamura, Tadatsugu Taniguchi, Kenya Honda

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   107 ( 22 )   10154 - 10159   2010.6

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.1005599107

    Web of Science

    researchmap

  • Regulation of immunity and oncogenesis by the IRF transcription factor family Invited Reviewed

    David Savitsky, Tomohiko Tamura, Hideyuki Yanai, Tadatsugu Taniguchi

    CANCER IMMUNOLOGY IMMUNOTHERAPY   59 ( 4 )   489 - 510   2010.4

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1007/s00262-009-0804-6

    Web of Science

    researchmap

  • HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses Reviewed

    Hideyuki Yanai, Tatsuma Ban, ZhiChao Wang, Myoung Kwon Choi, Takeshi Kawamura, Hideo Negishi, Makoto Nakasato, Yan Lu, Sho Hangai, Ryuji Koshiba, David Savitsky, Lorenza Ronfani, Shizuo Akira, Marco E. Bianchi, Kenya Honda, Tomohiko Tamura, Tatsuhiko Kodama, Tadatsugu Taniguchi

    NATURE   462 ( 7269 )   99 - U110   2009.11

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/nature08512

    Web of Science

    researchmap

  • A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA Reviewed

    Myoung Kwon Choi, ZhiChao Wang, Tatsuma Ban, Hideyuki Yanai, Yan Lu, Ryuji Koshiba, Yukana Nakaima, Sho Hangai, David Savitsky, Makoto Nakasato, Hideo Negishi, Osamu Takeuchi, Kenya Honda, Shizuo Akira, Tomohiko Tamura, Tadatsugu Taniguchi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   106 ( 42 )   17870 - 17875   2009.10

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.0909545106

    Web of Science

    researchmap

  • Critical role for constitutive type I interferon signaling in the prevention of cellular transformation Reviewed

    Hui-min Chen, Nobuyuki Tanaka, Yukiko Mitani, Eri Oda, Hiroaki Nozawa, Jian-zhong Chen, Hideyuki Yanai, Hideo Negishi, Myoung Kwon Choi, Toshiroh Iwasaki, Hiroyuki Yamamoto, Tadatsugu Taniguchi, Akinori Takaoka

    CANCER SCIENCE   100 ( 3 )   449 - 456   2009.3

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/j.1349-7006.2008.01051.x

    Web of Science

    researchmap

  • Regulation of the cytosolic DNA-sensing system in innate immunity: a current view Invited Reviewed

    Hideyuki Yanai, David Savitsky, Tomohiko Tamura, Tadatsugu Taniguchi

    CURRENT OPINION IN IMMUNOLOGY   21 ( 1 )   17 - 22   2009.2

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.coi.2009.01.005

    Web of Science

    researchmap

  • A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity Reviewed

    Hideo Negishi, Tomoko Osawa, Kentaro Ogami, Xinshou Ouyang, Shinya Sakaguchi, Ryuji Koshiba, Hideyuki Yanai, Yoshinori Seko, Hiroshi Shitara, Keith Bishop, Hiromichi Yonekawa, Tomohiko Tamura, Tsuneyasu Kaisho, Choji Taya, Tadatsugu Taniguchi, Kenya Honda

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   105 ( 51 )   20446 - 20451   2008.12

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.0810372105

    Web of Science

    researchmap

  • [IRF family transcription factors and host defense signaling]. Reviewed

    Yanai H, Taniguchi T

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   53 ( 10 )   1231 - 1238   2008.8

    　More details

  • Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules Reviewed

    ZhiChao Wang, Myoung Kwon Choi, Tatsuma Ban, Hideyuki Yanai, Hideo Negishi, Yan Lu, Tomohiko Tamura, Akinori Takaoka, Kazuko Nishikura, Tadatsugu Taniguchi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   105 ( 14 )   5477 - 5482   2008.4

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.0801295105

    Web of Science

    researchmap

  • A cell-type-specific requirement for IFN regulatory factor 5 (IRF5) in Fas-induced apoptosis Reviewed

    Arnaud Couzinet, Kaoru Tamura, Hui-min Chen, Keishiro Nishimura, ZhiChao Wang, Yasuyuki Morishita, Kazuyoshi Takeda, Hideo Yagita, Hideyuki Yanai, Tadatsugu Taniguchi, Tomohiko Tamura

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   105 ( 7 )   2556 - 2561   2008.2

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.0712295105

    Web of Science

    researchmap

  • The IRF family transcription factors in immunity and oncogenesis Invited Reviewed

    Tomohiko Tamura, Hideyuki Yanai, David Savitsky, Tadatsugu Taniguchi

    ANNUAL REVIEW OF IMMUNOLOGY   26   535 - 584   2008

    　More details

    Language：English   Publishing type：Part of collection (book)  

    DOI： 10.1146/annurev.immunol.26.021607.090400

    Web of Science

    researchmap

  • DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response Reviewed

    Akinori Takaoka, ZhiChao Wang, Myoung Kwon Choi, Hideyuki Yanai, Hideo Negishi, Tatsuma Ban, Yan Lu, Makoto Miyagishi, Tatsuhiko Kodama, Kenya Honda, Yusuke Ohba, Tadatsugu Taniguchi

    NATURE   448 ( 7152 )   501 - U14   2007.7

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/nature06013

    Web of Science

    researchmap

  • Effects of hydrophobic amino acid substitution in Pleurotus ostreatus proteinase A inhibitor 1 on its structure and functions as protease inhibitor and intramolecular chaperone Reviewed

    Shuichi Kojima, Akane Iwahara, Yuri Hisano, Hideyuki Yanai

    PROTEIN ENGINEERING DESIGN & SELECTION   20 ( 5 )   211 - 217   2007.5

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1093/protein/gzm013

    Web of Science

    researchmap

  • Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression Reviewed

    Hideyuki Yanai, Hui-min Chen, Takayuki Inuzuka, Seiji Kondo, Tak W. Mak, Akinori Takaoka, Kenya Honda, Tadatsugu Taniguchi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   104 ( 9 )   3402 - 3407   2007.2

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.0611559104

    Web of Science

    researchmap

  • ウイルス感染と宿主応答・宿主側の要因 MyD88依存的TLR下流シグナル経路におけるIRF-1の役割

    根岸 英雄, 柳井 秀元, 坂口 信也, 藤田 靖之, 篠原 正浩, 高柳 広, 大場 雄介, 谷口 維紹, 本田 賢也

    日本免疫学会総会・学術集会記録   36   207 - 207   2006.11

    　More details

    Language：English   Publisher：(NPO)日本免疫学会  

    researchmap

  • Evidence for licensing of IFN-gamma-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program Reviewed

    Hideo Negishi, Yasuyuki Fujita, Hideyuki Yanai, Shinya Sakaguchi, Xinshou Ouyang, Masahiro Shinohara, Hiroshi Takayanagi, Yusuke Ohba, Tadatsugu Taniguchi, Kenya Honda

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   103 ( 41 )   15136 - 15141   2006.10

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.0607181103

    Web of Science

    researchmap

  • Negative regulation of Toll-like-receptor signaling by IRF-4 Reviewed

    H Negishi, Y Ohba, H Yanai, A Takaoka, K Honma, K Yui, T Matsuyama, T Taniguchi, K Honda

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   102 ( 44 )   15989 - 15994   2005.11

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.0508327102

    Web of Science

    researchmap

  • Regulation of the type IIFN induction: a current view Invited Reviewed

    K Honda, H Yanai, A Takaoka, T Taniguchi

    INTERNATIONAL IMMUNOLOGY   17 ( 11 )   1367 - 1378   2005.11

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1093/intimm/dxh318

    Web of Science

    researchmap

  • IRF family transcription factors in type I interferon induction Invited Reviewed

    Hideyuki Yanai, Tatsuaki Mizutani, Takayuki Inuzuka, Kenya Honda, Akinori Takaoka, Tadatsugu Taniguchi

    International Congress Series   1285   104 - 113   2005.11

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.ics.2005.09.010

    Scopus

    researchmap

  • Inhibitor-assisted refolding of protease: A protease inhibitor as an intramolecular chaperone Reviewed

    S Kojima, A Iwahara, H Yanai

    FEBS LETTERS   579 ( 20 )   4430 - 4436   2005.8

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.febslet.2005.06.083

    Web of Science

    researchmap

  • Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction Reviewed

    K Honda, Y Ohba, H Yanai, H Negishi, T Mizutani, A Takaoka, C Taya, T Taniguchi

    NATURE   434 ( 7036 )   1035 - 1040   2005.4

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/nature03547

    Web of Science

    researchmap

  • IRF-7 is the master regulator of type-I interferon-dependent immune responses Reviewed

    K Honda, H Yanai, H Negishi, M Asagiri, M Sato, T Mizutani, N Shimada, Y Ohba, A Takaoka, N Yoshida, T Taniguchi

    NATURE   434 ( 7034 )   772 - 777   2005.4

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/nature03464

    Web of Science

    researchmap

  • Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors Reviewed

    A Takaoka, H Yanai, S Kondo, G Duncan, H Negishi, T Mizutani, S Kano, K Honda, Y Ohba, TW Mak, T Taniguchi

    NATURE   434 ( 7030 )   243 - 249   2005.3

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/nature03308

    Web of Science

    researchmap

  • Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling Reviewed

    K Honda, H Yanai, T Mizutani, H Negishi, N Shimada, N Suzuki, Y Ohba, A Takaoka, WC Yeh, T Taniguchi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   101 ( 43 )   15416 - 15421   2004.10

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1079/pnas.1016933101

    Web of Science

    researchmap

  • Selective contribution of IFN-alpha/beta signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection Reviewed

    K Honda, S Sakaguchi, C Nakajima, A Watanabe, H Yanai, M Matsumoto, T Ohteki, T Kaisho, A Takaoka, S Akira, T Seya, T Taniguchi

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   100 ( 19 )   10872 - 10877   2003.9

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.1934678100

    Web of Science

    researchmap

  • Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence Reviewed

    A Takaoka, S Hayakawa, H Yanai, D Stoiber, H Negishi, H Kikuchi, S Sasaki, K Imai, T Shibue, K Honda, T Taniguchi

    NATURE   424 ( 6948 )   516 - 523   2003.7

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/nature01850

    Web of Science

    researchmap

  • Accelerated refolding of subtilisin BPN ' by tertiary-structure-forming mutants of its propeptide Reviewed

    S Kojima, H Yanai, K Miura

    JOURNAL OF BIOCHEMISTRY   130 ( 4 )   471 - 474   2001.10

    　More details

    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1093/oxfordjournals.jbchem.a003008

    Web of Science

    researchmap

▼display all

MISC

▼display all

Industrial property rights

Awards

  • JSICR学会奨励賞

    2019.8   日本インターフェロンサイトカイン学会  

    柳井 秀元

    　More details

  • JSI Young Investigator Award

    2013  

    YANAI Hideyuki

    　More details

Research Projects

  • 自己由来分子による炎症・免疫応答系の調節機構の解明と関連病態制御の基盤構築

    Grant number：24H00606  2024.4 - 2027.3

    日本学術振興会  科学研究費助成事業  基盤研究(A)

    谷口 維紹, 大澤 毅, 衞藤 翔太郎, 中島 由希, 柳井 秀元

    　 More details

    Grant amount：\40040000 （ Direct Cost: \30800000 、 Indirect Cost：\9240000 ）

    researchmap

  • Elucidation of the pros and cons of recognition of tumor-derived molecules by innate immune receptors

    Grant number：23H04772  2023.4 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Transformative Research Areas (A)

    　 More details

    Grant amount：\7020000 （ Direct Cost: \5400000 、 Indirect Cost：\1620000 ）

    researchmap

  • Elucidation of self-derived molecules involved in the induction and progression of inflammatory disorders

    Grant number：23K24149  2022.4 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    　 More details

    Grant amount：\13130000 （ Direct Cost: \10100000 、 Indirect Cost：\3030000 ）

    researchmap

  • 自己炎症の誘導・遷延化に関わる自己細胞由来分子群の解明

    Grant number：22H02887  2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    柳井 秀元

    　 More details

    Grant amount：\13130000 （ Direct Cost: \10100000 、 Indirect Cost：\3030000 ）

    researchmap

  • ダメージ関連分子による炎症・免疫応答系の制御機構の解明

    Grant number：20H00504  2020.4 - 2024.3

    日本学術振興会  科学研究費助成事業  基盤研究(A)

    谷口 維紹, 半谷 匠, 柳井 秀元

    　 More details

    Grant amount：\43940000 （ Direct Cost: \33800000 、 Indirect Cost：\10140000 ）

    本研究の目的は、自己由来分子による炎症・免疫応答の調節機構を解明し、その破綻としての各種疾患の発症についての理解を深めることにある。死細胞やスト レスを受けた細胞からダメージ関連分子パターン(Damage-associated molecular patterns; DAMPs)と呼ばれる自己由来分子が放出され、それらが炎症・免疫系を調節することが注目されつつある。しかしながらその本体や作用機構には未知の点が多い。申請者らは、代表的なDAMPであるHMGB1(High-mobility group box-1 protein)の機能解析を推進するとともに、TCTP(Translationally-controlled tumor protein)やU11 small nuclear RNA(U11 snRNA)をはじめとする新規DAMP分子群を独自に同定している。本年度において、細胞外HMGB1の機能を解析するため、恒常的にHMGB1を細胞外に放出させる仕組みを組み込んだコンディショナルノックインマウスを作成し、交配を進めている。また、細胞外に放出されたTCTPが腫瘍微小環境中に骨髄由来免疫抑制細胞（PMN-MDSCs）をリクルートし、抗腫瘍免疫応答を抑制することを突き止めた。従って、細胞外TCTPは腫瘍増殖を促進することを明らかにした。またさらに、TCTPに対する阻害剤の投与により腫瘍増殖が抑制されることも見出した。このように新規DAMPとしてTCTPの解析を進める一方、免疫応答制御に関わる新たなDAMPsについて同定と解析も進めた。

    researchmap

  • Role of extracellular HMGB1 in promotion of inflammation

    Grant number：18K07167  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Yanai Hideyuki

    　 More details

    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    In this study, we examined the mechanism of how HMGB1 promotes neutrophil migration and the importance of HMGB1 in the pathogenesis of inflammatory diseases. Interestingly, administration of HMGB1-targeting inhibitor ISM ODN into ConA-treated mice suppressed liver inflammation and neutrophil infiltration. ISM ODN treatment also reduced B16F10 tumor growth, suggesting that the promotion of neutrophil infiltration by HMGB1 augments the liver inflammation and tumor growth. To further study HMGB1-induced neutrophil migration in vivo, we generated knock-in mice that constantly release HMGB1 extracellularly.

    researchmap

  • Elucidation of the host's homeostatic responses by the regulation of immune system and its application to the prevention and treatment of immunological disorders

    Grant number：15H05787  2015.5 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (S)

    Taniguchi Tadatsugu

    　 More details

    Grant amount：\171990000 （ Direct Cost: \132300000 、 Indirect Cost：\39690000 ）

    In this research project, we aimed at elucidating the role of the immune system in maintaining the body’s homeostasis to establish a basis for disease prevention and treatment by regulating harmful immune responses. We performed the research project by two approaches: One is to study the role of self-derived immune regulatory molecules in inflammation and cancer and, the other, search for the target(s) of a chemical compound K69, which we originally discovered as a suppressor of autoimmunity. From these approaches, we identified HMGB1 as the critical regulator of inflammatory diseases and cancer. We also identified U11 snRNA as the target of the K69 and a potent activator of the Toll-like receptor-7 (TLR7) pathway. On the basis of these findings, we developed small RNAs that potently activate or inhibit TLR7. These results might introduce a new approach to the regulation of immune responses mediated by self-derived molecules in the prevention and treatment of diseases.

    researchmap

  • 自己由来分子による炎症･免疫応答系の制御機構の解明

    Grant number：15H02514  2015.4 - 2016.3

    日本学術振興会  科学研究費助成事業  基盤研究(A)

    谷口 維紹, 柳井 秀元, 根岸 英雄, 西尾 純子

    　 More details

    Grant amount：\14820000 （ Direct Cost: \11400000 、 Indirect Cost：\3420000 ）

    本研究は、自己由来分子による炎症・免疫応答の調節機構を解明し、その破綻としての各種疾患の発症についての理解を深め、炎症・免疫疾患発症機構における新たなパラダイムの創出を目指すものである。細胞が様々な刺激を受けるとタンパク、核酸などの多様な成分が放出され、それらが炎症・免疫系を調節することが注目されつつある。このような細胞応答シグナルのバランスが破綻することが種々の疾患の発症に繋がると考えられるが、自己由来成分の本態や作用機構には未知の点が多い。我々は既に、代表的な自己細胞由来炎症誘発タンパクであるHMGB1(High-mobility group box 1)の機能解析を推進するとともに、新たな炎症誘発性低分子RNAや抑制性脂質成分等を同定し、それらの作用機序の解明を目指すべく、検討を開始した。一方で、本研究内容を含んだ新たな研究計画（基盤研究S）が採択されたことにより、本研究内容を新たな研究計画に組み込んだ形で推進を行うため、本研究計画を廃止するに至った。

    researchmap

  • Analysis of newly identified nucleic acid-recognition molecules in innate immunity

    Grant number：24590574  2012.4 - 2015.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    YANAI Hideyuki

    　 More details

    Grant amount：\5330000 （ Direct Cost: \4100000 、 Indirect Cost：\1230000 ）

    Pathogen infection induces robust innate immune responses. Nucleic acids from pathogens such as viruses and bacteria are recognized by nucleic acid-recognition receptors and evokes the activation of innate immune responses. We searched for host cell molecules which are involved in the responses and identified two RNA-binding motif-containing molecules, namely NAS1 and NAS2. In this research we established conditional knockout mice lines of NAS1 and NAS2 and analyzed the contribution of NAS1 and NAS2 to nucleic acid-mediated innate immune responses. Interestingly, we have found that the activation of type I IFN genes and IL-12p40 gene by B-DNA or CpG-B stimulation were impaired in NAS1 KO dendritic cells. In addition, NAS1 KO mice were easily succumbed to HSV-1 infection and Listeria monocytegenes infection. These results indicate that NAS1 is critical to host defense against pathogen infection.

    researchmap

  • Elucidation and control of the carcinogenic spiral that results from inflammation and immune responses

    Grant number：22114007  2010.4 - 2015.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    TANIGUCHI Tadatsugu, YANAI Hideyuki, NEGISHI Hideo

    　 More details

    Grant amount：\125710000 （ Direct Cost: \96700000 、 Indirect Cost：\29010000 ）

    The aim of the project was to investigate the mechanisms of inflammation and immune responses caused by self-derived molecules in the regulation of carcinogenic spiral. First, we found that the innate immune receptor Dectin-1 expressed on dendritic cells and macrophages is critical to NK-mediated killing of tumor cells that express high-level N-glycan structures. Second, we focused on HMGB1, known to cause inflammatory responses, for its role in inflammation and cancer. For this study, we first generated mice that allow conditional inactivation of the HMGB1 gene in a cell- and tissue-specific manner. We adduced evidence that intracellular HMGB1 contributes to the protection of mice from endotoxemia and bacterial infection. In addition, we also found that the loss of HMGB1 in the liver results in dramatic reduction of liver metastasis of tumor cells. Overall, these results suggest a novel direction in the control of carcinogenic spiral by the immune system.

    researchmap

  • The role of IRF transcription factor family in inflammation-associated tumorigenesis

    Grant number：21390089  2009 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    TAMURA Tomohiko, MAEDA Shin, YANAI Hideyuki, HOTTA Chie, KUROTAKI Daisuke

    　 More details

    Grant amount：\18460000 （ Direct Cost: \14200000 、 Indirect Cost：\4260000 ）

    A role for chronic inflammation in tumorigenesis is now generally accepted, and nuclear factorκ-B(NF-κB) has been implicated in the cause or exacerbation of inflammation-induced cancers. The present study demonstrates that the interferon regulatory factor(IRF) transcription factor family, which can be activated simultaneously with NF-κB by innate immune stimuli, possesses tumor-suppressing abilities in inflammation-induced cancers.

    researchmap

  • Innate immune system activation and regulation via DNA receptors.

    Grant number：19209016  2007 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (A)

    TANIGUCHI Tadatsugu, YANAI Hideyuki

    　 More details

    Grant amount：\45630000 （ Direct Cost: \35100000 、 Indirect Cost：\10530000 ）

    Recently, we had identified a novel cytosolic DNA sensing molecule, DAI (DNA-dependent activator of IRFs). We analyzed the activating mechanism of DAI by cytosolic DNA stimulation and we found a new DNA binding domain and phosphorylation sites in DAI protein. These domain and amino acid residues are turned out to be important for DNA-mediated activation of innate immune responses. To investigate further the role of DAI in innate immune responses in vivo, we generated mice deficient in Dai gene. Dai^<-/-> mice grew normally with normal cellular population in lymphoid organs compared to those of wild-type control mice. We analyzed the role of DAI in innate immune responses and found defects in mRNA induction levels of some antiviral genes in Dai^<-/-> cells.

    researchmap

  • The role of transcription factor IRF-3 in cardiac disease

    Grant number：19590492  2007 - 2008

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    YANAI Hideyuki, TSUSHIMA Kensuke

    　 More details

    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    researchmap

  • TLRシグナル伝達におけるIRF-5活性化機構の解明

    Grant number：18890054  2006 - 2007

    日本学術振興会  科学研究費助成事業  若手研究(スタートアップ)

    柳井 秀元

    　 More details

    Grant amount：\2420000 （ Direct Cost: \2420000 ）

    生体防御において免疫系の賦活化は必須であり、また適時の適当な免疫応答が恒常性維持に重要である。IRF(インターフェロン制御因子)ファミリー転写因子はインターフェロン誘導のみならず、種々の免疫反応の誘導にも重要な転写因子であり、その異常によって自己免疫反応を含め、免疫応答の破綻をきたす。IRF-5は病原体関連分子の認識受容体であるToll-like receptor(TLR)の刺激により活性化され、炎症性サイトカインの誘導に重要な転写因子であることを明らかにしたが、TLR下流でのIRF-5活性化機構は不明である。この活性化機構のメカニズムの一端を解き明かすべく検討を進めた。まず、IRF-5遺伝子欠損マクロファージを用いてTLR刺激での誘導遺伝子についてマイクロアレイ解析によって検討したところ、これまで報告した炎症性サイトカインのみならず、その他の誘導遺伝子においても顕著な減弱がみとめられる遺伝子が複数存在することが明らかとなった。さらに興味深いことには、刺激において通常は発現が抑制されるような遺伝子群が、IRF-5遺伝子欠損細胞において、むしろ誘導が増強されていることが見いだされた。これらはプロテアーゼなど代謝に必要な酵素群の遺伝子であった。通常は感染時などに抑制されるべき分子が、逆に誘導されることから、IRF-5は自己を攻撃することに繋がる分子の発現を抑える役割を持っていることが示唆された。最近IRF-5について、自己免疫疾患の一つである全身性ループスエリテマトーデス(SLE)との関連が指摘されており、今後はこのIRF-5の遺伝子誘導の抑制機能にも焦点をあてつつ、研究計画に沿って検討を進めていく予定である。

    researchmap

  • インターフェロン制御因子ファミリー活性化の時空間ダイナミクスの解析

    Grant number：18060008  2006 - 2007

    日本学術振興会  科学研究費助成事業  特定領域研究

    本田 賢也, 柳井 秀元

    　 More details

    Grant amount：\7000000 （ Direct Cost: \7000000 ）

    9つあるlnterferon regutatory factor(IRF)ファミリーメンバーの内IRF3・IRF7は、細胞に侵入した病原体を認識し、活性化することでインターフェロンの産生に重要な役割を果たす。そのメカニズムは、病原体の特徴ある核酸構造と異常な細胞内局在を、Toll like receptor(TLR)や細胞内RNA認識受容体が認識し、IRF活性化へとシグナルを変換するためと考えられているが、病原体由来のDNAの認識メカニズムは、まだ十分には理解されていない。
    そこで、IRF3・IRF7の活性化を促す細胞内DNAセンサーの同定を試みた。IRF7を効果的に活性化できる細胞である形質細胞様樹状細胞からcDNAと、それがコードする蛋白質が結合した形のライブラリーを構築した(CFPDライブラリー)。このCFPDライブラリーをリガンド(非メチル化DNA)を結合させたカラムにアプライし、非メチル化DNAに特異的に結合する分子を解析したところ、いくつかの核酸結合ドメインを持つ分子が同定された。同定された分子は核小体周辺の核内に局在する分子であった。そこで、そのノックダウン細胞の樹立とノックアウトマウスの作製を試みた。現在までに、当該分子のノックダウン方法は確立でき、同時にノックアウトES細胞の作製は終了し、キメラマウスを作製できた。
    また一方、IRF3・IRF7のみならず、 IRF2およびIRF5の血球分化やTLRシグナルにおける役割をさらに詳細に検討した。IRF2が赤血球分化におけるアポトーシス抑制に必須であること、および、 IRF5が複数のTLRシグナルの協調作用において必須の作用があることを見いだし、論文として報告した。

    researchmap

  • Informatory expression system connecting cancer and immunity.

    Grant number：17012005  2005 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research on Priority Areas

    TANIGUCHI Tadatsugu, TAKAOKA Akinori, TAMURA Tonohiko, HONDA Kenya, OOBA Yuusuke, YANAI Hideyuki

    　 More details

    Grant amount：\417200000 （ Direct Cost: \417200000 ）

    We investigated biological mechanisms and role of effecter molecules, e.g. interferons, IRFs and Noxa. It revealed that these molecules are involved in transformation, apoptosis induction and metastasis signaling pathways. We also found the cross-talk pathway between TLRs signaling. Moreover, we identified DAI and HMGB1, 2, 3 are important for the nucleic-acid mediated innate immune responses. Since these pathways regulate tumorgenesis and exacerbation, our findings will be proved to be useful for the development of novel tumor therapy in near future.

    researchmap

  • 構成的に発現しているI型IFNシグナルによる癌化抑制メカニズムの解明

    Grant number：03J61523  2003 - 2004

    日本学術振興会  科学研究費助成事業  特別研究員奨励費

    柳井 秀元

    　 More details

    Grant amount：\1800000 （ Direct Cost: \1800000 ）

    これまで構成的なIFN-α/βのシグナルの異常が細胞のトランスフォーメーションを引き起こすことを見出し、新しい発がんの制御機構の解明を目指して、この構成的なIFN-α/βのシグナルのがん化抑制の作用について詳細な検討を進めてきた.そこでさらに,生体内でもっとも強力にIFN-α/βを産生する細胞として知られているpDCにおける大量のIFN-α/βの産生メカニズムについて検討することにした.pDCにおいては非メチル化DNAや一本鎖RNAなどを認識し,Toll様受容体であるTLR9やTLR7(8)を介してMyD88依存性にIFN-α/βが大量産生される事が報告されていた.今回,我々は,このTLR7およびTLR9下流でのIFN遺伝子誘導において,従来ウイルス感染によるIFN遺伝子誘導に必須であることが知られているIRF-3およびIRF-7転写因子の関連性について検討を行った.その結果,FRET(fluorescence resonance energy transfer)解析や免疫沈降実験により,細胞質においてIRF-7がMyD88と会合することを見出した.一方IRF-3はMyD88とは会合しないことが示された.また,luciferase reporter assayやCpG-A ODN(oligodeoxynucleotide)刺激による核移行の解析の結果,MyD88依存性にIRF-7が活性化され,核移行することも明らかとなった.またIRF-7はTRAF6がIRF-7と会合し,その活性化に関与することも見出した.さらに,従来,IRAK4はMyD88と会合し,下流のNF-kB活性化につながる必須の分子であることが知られていたが,今回MyD88欠損マウス由来のpDCsと同様にIRAK4欠損マウス由来のpDCsにおいてCpG-A ODNおよび一本鎖RNA刺激によるIFN-α産生誘導が全く消質することもわかり,TLR9-MyD88下流におけるIRF-7の活性化にIRAK4が関与していることも示唆された.さらにIRF-7欠損マウスを作成して解析を進めたところ,IRF-7遺伝子欠損マウス由来pDCにおいては非メチル化DNAや一本鎖RNA刺激によるIFN産生が全く認められなかった.これらの結果,おそらくTLR7/9直下においてMyD88をはじめIRF-7,TRAF6やIRAK4を含む複合体(CTTP)が何らかの制御のもとに,少なくとも1つはIRF-7を介したIFN産生誘導経路と,もう一つは炎症性サイトカイン発現経路を分岐しているものと考えられた.

    researchmap

▼display all

Teaching Experience