title: CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation.
abstract: 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.
authors.affiliation: Institute of Life Science, Kurume University, Kurume 839-0861, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Hanada
authors.forename: K
authors.initials: K
authors.lastname: Mitsuyama
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
authors.forename: S
authors.initials: S
authors.lastname: Kamizono
authors.forename: T
authors.initials: T
authors.lastname: Hoshino
authors.forename: M
authors.initials: M
authors.lastname: Kubo
authors.forename: A
authors.initials: A
authors.lastname: Yamashita
authors.forename: M
authors.initials: M
authors.lastname: Okabe
authors.forename: K
authors.initials: K
authors.lastname: Takeda
authors.forename: S
authors.initials: S
authors.lastname: Akira
authors.forename: S
authors.initials: S
authors.lastname: Matsumoto
authors.forename: A
authors.initials: A
authors.lastname: Toyonaga
authors.forename: M
authors.initials: M
authors.lastname: Sata
authors.forename: A
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D003092:Colitis / Q000209:etiology* / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000209:etiology / Q000378:metabolism; D003424:Crohn Disease / Q000209:etiology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016264:Dextran Sulfate / Q000009:adverse effects; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000209:etiology* / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D009924:Organ Culture Techniques; D011506:Proteins / Q000378:metabolism*; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D015431:Weight Loss
chemical_list: D004268:DNA-Binding Proteins; D015850:Interleukin-6; D011506:Proteins; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016753:Interleukin-10; D016264:Dextran Sulfate