Functional analyses on roles of intetferon-IRF-family transcriptional factor

• Project/Area Number: 16017220
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: University of Tokyo
• Principal Investigator: TAKAOKA Akinori Univ. of Tokyo, Grad. Sch.of Med., Lecturer, 大学院医学系研究科, 講師 (30323611)
• Co-Investigator(Kenkyū-buntansha): HONDA Kenya Univ.of Tokyo, Grad. Sch. of Med., Research Lecturer, 大学院医学系研究科, 助手 (60334231)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥13,500,000 (Direct Cost: ¥13,500,000); Fiscal Year 2005: ¥6,400,000 (Direct Cost: ¥6,400,000); Fiscal Year 2004: ¥7,100,000 (Direct Cost: ¥7,100,000)
• Keywords: interferon / IRF family / dendritic cells / apoptosis / Toll-like receptor / p53 / innate immunity / antiviral defense / ウイルス感染 / 形質細胞様樹状細胞 / 炎症性サイトカイン / 転写因子

Research Abstract

In this study, we analyzed the molecular mechanism for antiviral defense triggered by interferon-α / (IFN-α/β) and the signalling pathways which lead to type I IFN gene induction by TLR activation. In particular, we focused on IFN-regulatory factors (IRFs), which are known to be essential factors upon viral infection, and have elucidated several novel roles of the IFN-IRF system in activation of innate immune response. First, we found that the level of p53 gene, which is known to encode a tumor suppressor, is upregulated by IFN treatment through activation of ISGF3 transcriptional complex, contributing to enhancement of p53 response to stress signals. We showed that p53 is phosphorylated and activated upon viral infection, and that p53 is essentially involved in the induction of apoptosis in virally infected cells. This result demonstrated an interrelationship between IFN-α/β signaling and p53-mediated response, which provided a novel aspect in terms of a linkage between tumor suppression and immunity. Second, we analyzed various hideficient mice to show that IRF-7 mediates a novel MyD88-dependent pathway for the induction of type I IFN gene expression by TLR9 subfamily members in plasmacytoid dendritic cells (pDCs). In addition, we found a spaciotemporal regulation, by which pDCs are capable to produce high levels of IFN- α/β. On the other hand, IRF-5 is found to be essentially involved in TLR-mediated production of proinflammatory cytokines. Recently, we also found that IRF-5 is activated upon viral infection and plays a role in virus-induced apoptosis in a distinct manner from p53. Another IRF-family member, IRF-4, is shown to be a negative regulator of IRF-5 by competitively inhibiting the interaction of IRF-5 with MyD88. Thus, we demonstrated that IRF-family transcriptional factors are critical downstream mediators of TLRs to regulate the activation of innate immune response.

Research Products

• [Journal Article] Pole of IFN regulatory factor 5 transcription factor in anitiviral immunity and tumor suppression. (2007)
  • Author(s): Yanai H, Chen HM, Inuzaka T, Koado S, Mak TW, Takaoka A, Honda K, Taniguchi T.
  • Journal Title: Proc Natl Acad Sci U S A. 104 Pages: 3402-3407
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression. (2007)
  • Author(s): Yanai, H., Chen, H.M., Inuzuka, T., Kondo, S., Mak, Takaoka, A., Honda, K., Taniguchi, T.
  • Journal Title: Proc. Natl. Acad. Sci. USA 104 Pages: 3402-3407
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interferon signaling network in innate defense. (2006)
  • Author(s): Takaoka, A., Yanai, H.
  • Journal Title: Cellular Microbiology (印刷中)
• [Journal Article] Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors (2005)
  • Author(s): Takaoka A., Yanai H., Kondo S., Duncan G., Negishi H., Mizutani T., Kano S., Honda K., Ohba Y., Mak T.M., Taniguchi T.
  • Journal Title: Nature 434 Pages: 243-249
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. (2005)
  • Author(s): Honda K., Ohba, Y., Yanai, H., Negishi H., Mizutani, T., Takaoka, A., Taya, C., Taniguchi, T
  • Journal Title: Nature 434 Pages: 1035-1040
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] IRF-7 is the master regulator of type-I interferon-dependent immune responses. (2005)
  • Author(s): Honda, K., Yanai, H., Negishi, H., Asagiri, M., Sato, M., Mizutani, T., Shimada, N., Ohba, Y., Takaoka, A., Yoshida, N., Taniguchi, T.
  • Journal Title: Nature 434 Pages: 727-777
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Negative regulation of Toll-like-receptor signaling by IRF-4. (2005)
  • Author(s): Negishi H, Ohba Y, Yanai H, Takaoka A, Honma K, Yui K, Matsuyama T, Taniguchi T, Honda K.
  • Journal Title: Proc Natl Acad Sci U S A. 102 Pages: 15989-15994
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Integral role of IRF-5 in the gene nduction programme activated by Toll-like receptors. (2005)
  • Author(s): Takaoka, A., Yanai, H., Kondo, S., Duncan, G., Negishi, Mizutani, T., Kano, S., Honda, K., Ohba, Y., Mak, T.M., Taniguchi, T.
  • Journal Title: Nature 434 Pages: 243-249
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type I nterferon induction. (2005)
  • Author(s): Honda, K., Ohba, Y., Yanai, H., Negishi, H., Mizutani, T., Takaoka, A., Taya, C., Taniguchi, T.
  • Journal Title: Nature 434 Pages: 1035-1040
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Negative regulation of Toll-like-receptor signaling by IRF-4. (2005)
  • Author(s): Negishi, H., Ohba, Y., Yanai, H., Takaoka, A., Honma, Yui, K., Matsuyama, T., Taniguchi, T., Honda, K.
  • Journal Title: Proc. Natl. Acad. Sci. USA 120 Pages: 15989-15994
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. (2005)
  • Author(s): Takaoka, A., Yanai, H., Kondo, S., Duncan, G., Negishi, H., Mizutani, T., Kano, S., Honda, K., Ohba, Y., Mak, T.M., Taniguchi, T.
  • Journal Title: Nature Vol.434 Pages: 243-249
• [Journal Article] Type I interferon system and IRF family of transcription factors in host defense regulation. (2005)
  • Author(s): Taniguchi, T., Takaoka, A.
  • Journal Title: Proc.Jpn.Acad., Ser.B Vol.81 Pages: 1-13
  • NAID: 130000093822
• [Journal Article] IRF-7 is the master regulator of type-I interferon-dependent immune responses. (2005)
  • Author(s): Honda, K., Yanai, H., Negishi, H., Asagiri, M., Sato, M., Mizutani, T., Shimada, N., Ohba, Y., Takaoka, A., Yoshida, N., Taniguchi, T.
  • Journal Title: Nature Vol.434 Pages: 772-777
• [Journal Article] Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. (2005)
  • Author(s): Honda, K., Ohba, Y., Yanai, H., Negishi, H., Mizutani, T., Takaoka, A., Taya, C., Taniguchi, T.
  • Journal Title: Nature Vol.434 Pages: 1035-1040
• [Journal Article] Negative regulation of Toll-like receptor signaling by IRF-4.Proc.Natl.Acad.Sci.USA. (2005)
  • Author(s): Negishi, H., Ohba, Y., Yanai, H., Takaoka, A., Honma, K., Yui, K., Matsuyama, T., Taniguchi, T., Honda, K.
  • Journal Title: Proc.Natl.Acad.Sci.USA. Vol.102 Pages: 15989-15994
• [Journal Article] Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. (2005)
  • Author(s): Takaoka.A., Yanai, H., Kondo, S., Duncan, G., Negishi, H., Mizutani, T., Kano, S., Honda, K., Ohba, Y, Mak, T.M., Taniguchi, T.
  • Journal Title: Nature 434・7030 Pages: 243-249
• [Journal Article] Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. (2004)
  • Author(s): Honda, K., Yanai, H, Mizutani, T, Negishi, H., Shimada, N, Suzuki, N, Obba, Y, Takaoka.A., Wen-Chen Yeh, Taniguchi, T.
  • Journal Title: Proc.Natl.Acad.Sci.USA 101・43 Pages: 15416-15421
• [Journal Article] Integration of IFN-α/β sinalling to p53 responses in tumour suppression and anitiviral defense. (2003)
  • Author(s): Takaoka, A., Hayakawa, S., Yanai, H., Stoiber, D., Negishi H., Kikuchi, H., Sasaki, S., Imai, K., Shibue, T., Honda, K., Taniguchi, T.
  • Journal Title: Nature 424 Pages: 516-526
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Integration of IFN-a/f3 signalling to p53 responses in tumour suppression and antiviral defense. (2003)
  • Author(s): Takaoka, A., Hayakawa, S., Yanai, H., Stoiber, D., Negishi, H., Kikuchi, H., Sasaki, S., Imai, K., Shibue, T., Honda, K., Taniguchi, T.
  • Journal Title: Nature 424 Pages: 516-526
  • Description: 「研究成果報告書概要(欧文)」より