Cis3/Socs3/Ssi3 Plays a Negative Regulatory Role in Stat3 Activation and Intestinal Inflammation

DOI PDF 被引用文献20件
  • Asuka Suzuki
    aInstitute of Life Science, Kurume University, Kurume 839-0861, Japan
  • Toshikatsu Hanada
    aInstitute of Life Science, Kurume University, Kurume 839-0861, Japan
  • Keiichi Mitsuyama
    bSecond Department of Internal Medicine, Faculty of Medicine, Kurume University, Asahi-machi, Kurume 830-0011, Japan
  • Takafumi Yoshida
    aInstitute of Life Science, Kurume University, Kurume 839-0861, Japan
  • Shintaro Kamizono
    aInstitute of Life Science, Kurume University, Kurume 839-0861, Japan
  • Tomoaki Hoshino
    cFirst Department of Internal Medicine, Faculty of Medicine, Kurume University, Asahi-machi, Kurume 830-0011, Japan
  • Masato Kubo
    eDivision of Immunobiology, Research Institute for Biological Sciences, Science University of Tokyo, Noda 278-0022, Japan
  • Atsuko Yamashita
    fGenome Information Research Center, Osaka University, Osaka 565-0871, Japan
  • Masaru Okabe
    fGenome Information Research Center, Osaka University, Osaka 565-0871, Japan
  • Kiyoshi Takeda
    gResearch Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
  • Shizuo Akira
    gResearch Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
  • Satoshi Matsumoto
    hYakult Central Institute for Microbiological Research, Kunitachi, Tokyo 186-8650, Japan
  • Atsushi Toyonaga
    bSecond Department of Internal Medicine, Faculty of Medicine, Kurume University, Asahi-machi, Kurume 830-0011, Japan
  • Michio Sata
    bSecond Department of Internal Medicine, Faculty of Medicine, Kurume University, Asahi-machi, Kurume 830-0011, Japan
  • Akihiko Yoshimura
    aInstitute of Life Science, Kurume University, Kurume 839-0861, Japan

抄録

<jats:p>Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription (STAT) transcription factors. We recently identified two intrinsic Janus kinase (JAK) inhibitors, JAK binding protein (JAB; also referred to as suppressor of cytokine signaling [SOCS1]/STAT-induced STAT inhibitor [SSI1]) and cytokine-inducible SH2 protein (CIS)3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, STAT3 was most strongly tyrosine phosphorylated in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of colitis as well as STAT3 activation was significantly reduced in IL-6–deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice as well as several T cell–dependent colitis models. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.</jats:p>

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