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 - Institute for Virus Research
Infection and Prevention
Biological Responses
The innate immune system directly recognizes infection of pathogens including viruses and bacteria via microbial sensors such as Toll-like receptors (TLRs). The TLR signaling results in the production of cytokines and evokes inflammation. We are studying the molecular mechanisms of inflammation caused by innate immunity by using model mice. We are focusing on 1) Regulation of cytokine production by RNA stability control. 2) Mechanisms of TLR signaling. 3)Transcriptional control in response to TLR stimulation.

  Osamu Takeuchi
Professor
Research and Education
Viral and bacterial infection is initially recognized by the host innate immune system. Pattern recognition receptors such as Toll-like receptors (TLRs) initiate intracellular signaling pathways leading to the production of cytokines and causing inflammation (Fig. 1). Inflammation is related not only to infectious diseases, but also to various common diseases including autoimmune disease, cancer and metabolic disorders. We are studying molecular mechanisms of inflammation from innate immunity point of view. Particularly we are focusing on transcriptional and posttranscriptional regulation of genes relating to inflammation. We recently identified that an adaptor molecule TANK is critical for preventing development of autoimmune glomerular nephritis by inhibiting TLR signaling. Also, we discovered an RNase, named Regnase-1, which is responsible for destabilizing cytokine mRNAs and prevention of autoimmune diseases (Fig. 2). Regnase-1 is rapidly degraded in response to TLR stimulation in a manner dependent on IKK-mediated phosphorylation (Fig. 1). We will study how the balance is taken between transcription and degradation (Takeuchi, Mino). We are also studying on inflammation and redox regulation (Masutani).
Graduate students in our lab will learn skills on molecular biology and immunology. We welcome young students who are interested in our research.


Infection and Prevention
Institute for Virus Research
Professor Osamu Takeuchi
Associate
 Professor


Hiroshi Masutani
Assistant
 Professor


Takashi Mino
TEL +81-75-751-4024
FAX +81-75-761-5766
e-mail otakevirus.kyoto-u.ac.jp
URL http://www.virus.kyoto-u.ac.jp/Lab/Takeuchi_HP/index.html
The Toll-like receptor signaling pathway, triggered by pathogen infection, is regulated by various intracellular molecules such as Regnase-1 and TANK. These molecules control levels of cytokines and inflammation appropriate.
Deficiency of TANK or Regnase-1 in mice leads to the development of autoimmune diseases via excess production of proinflammatory cytokines. TANK-deficient mice show glomerular nephritis (Left), and infiltration of immune cells to lung and liver was observed in Regnase-1-deficient mice (Right).
Laboratory members
Recent Publications
1. Iwasaki H, Takeuchi O*, Teraguchi S, Matsushita K, Uehata T, Kuniyoshi K, Satoh T, Saitoh T, Matsushita M, Standley DM, Akira S* (*correspondence). The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1. Nat Immunol. 12:1167-75, 2011
2. Miyake T, Satoh T, Kato H, Matsushita K, Kumagai Y, Vandenbon A, Tani T, Muta T, Akira S, Takeuchi O. IκBζ is essential for natural killer cell activation in response to IL-12 and IL-18. Proc Natl Acad Sci U S A. 107:17680-5, 2010
3. *Satoh T, *Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, Miyake T, Matsushita K, Okazaki T, Saitoh T, Honma K, Matsuyama T, Yui K, Tsujimura T, Standley DM, Nakanishi K, Nakai K, Akira S. (Equal contribution) The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol. 11:936-44, 2010
4. akeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 140:805-20, 2010
5. *Kawagoe T, *Takeuchi O, Takabatake Y, Kato H, Isaka Y, Tsujimura T, Akira S. (Equal contribution) TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis. Nat Immunol. 10:965-72, 2009
6. *Matsushita K, *Takeuchi O, Standley DM, Kumagai Y, Kawagoe T, Miyake T, Satoh T, Kato H, Tsujimura T, Nakamura H, Akira S. (Equal contribution) Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 458:1185-90, 2009