Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 528K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Suzuki, A. Articles by Yoshimura, A. Search for Related Content PubMed PubMed Citation Articles by Suzuki, A. Articles by Yoshimura, A. Social Bookmarking                            What's this?

Original Article

^a Institute of Life Science, Kurume University, Kurume 839-0861, Japan
^b Second Department of Internal Medicine, Faculty of Medicine, Kurume University, Asahi-machi, Kurume 830-0011, Japan
^c First Department of Internal Medicine, Faculty of Medicine, Kurume University, Asahi-machi, Kurume 830-0011, Japan
^d Department of Urology, Oita Medical University, Oita 879-5593, Japan
^e Division of Immunobiology, Research Institute for Biological Sciences, Science University of Tokyo, Noda 278-0022, Japan
^f Genome Information Research Center, Osaka University, Osaka 565-0871, Japan
^g Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
^h Yakult Central Institute for Microbiological Research, Kunitachi, Tokyo 186-8650, Japan
Institute of Life Science, Kurume University, Aikawa-machi 2432-3, Kurume 839-0861, Japan.81-942-31-521281-942-37-6313

yosimura{at}lsi.kurume-u.ac.jp

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.

Key Words: Janus kinase • CIS/SOCS • interleukin 6 • ulcerative colitis • negative regulation

© 2001 The Rockefeller University Press

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS