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STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice
  1. K Mitsuyama1,*,
  2. S Matsumoto3,*,
  3. S Rose-John3,
  4. A Suzuki1,
  5. T Hara2,
  6. N Tomiyasu1,
  7. K Handa1,
  8. O Tsuruta1,
  9. H Funabashi2,
  10. J Scheller3,
  11. A Toyonaga1,
  12. M Sata1
  1. 1Second Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
  2. 2Yakult Central Institute for Microbiological Research, Kunitachi, Tokyo, Japan
  3. 3Department of Biochemistry, Christian-Albrechts-Universiy, Kiel, Germany
  1. Correspondence to:
    Dr K Mitsuyama
    Second Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830–0011, Japan; ibd{at}


Background and aim: SAMP1/Yit mice spontaneously develops intestinal inflammation. Previously, we demonstrated that the signal transducer and activator of transcription (STAT)-3/suppressor of cytokine signalling (SOCS)-3 pathway is pivotal in human inflammatory bowel disease. In our studies in SAMP1/Yit mice, the aim was to investigate whether STAT3 activation contributes to ileitis and to examine the therapeutic effects of this signal blockade.

Methods: Intestinal expression of phospho-STAT3 in SAMP1/Yit mice and control AKR/J mice was examined by western blotting and immunohistochemistry. SOCS3 and interleukin 6 (IL-6) mRNA were determined by northern blotting and reverse transcription-polymerase chain reaction, respectively. We also examined the effects of intravenously injected hyper-IL-6, an IL-6/soluble IL-6 receptor fusion protein, and of soluble gp130-Fc, a specific inhibitor of soluble IL-6 receptor signalling, on STAT3 phosphorylation and disease severity in SAMP1/Yit mice.

Results: Phospho-STAT3 was expressed strongly during the disease course in SAMP1/Yit mice but only transiently in AKR/J mice. Phospho-STAT3 was localised to epithelial and mononuclear cells in the diseased intestine of SAMP1/Yit mice. SOCS3 as well as IL-6 mRNAs were expressed in affected intestine. Administration of hyper-IL-6 caused disease exacerbation and enhancement of STAT3 phosphorylation. In contrast, soluble gp130-Fc administration ameliorated the disease and suppressed STAT3 phosphorylation.

Conclusion: STAT3 signalling is critical in the development of intestinal inflammation in SAMP1/Yit mice. Blockade of this signalling pathway by soluble gp130-Fc may have therapeutic effects in inflammatory bowel disease.

  • DIG, digoxygenin
  • DSS, dextran sodium sulphate
  • EDTA, ethylenediaminetetraacetic acid
  • G3PDH, glyceraldehyde-3-phosphate dehydrogenase
  • hpf, high power field
  • IBD, inflammatory bowel disease
  • IL-6, interleukin 6
  • IL-6R, interleukin 6 receptor
  • sIL-6R soluble interleukin 6 receptor,
  • JAK, Janus kinase
  • MAPK, mitogen activated protein kinase
  • ML, mononuclear lymphocytes
  • PBS, phosphate buffered saline
  • PMN, polymorphonuclear cells
  • RT-PCR, reverse transcription-polymerase chain reaction
  • SCID, severe combined immunodeficiency
  • sgp130, soluble form of gp130
  • SOCS, suppressor of cytokine signalling
  • SPF, specific pathogen free
  • STAT, signal transducer and activator of transcription
  • interleukin 6
  • gp130
  • signal transducer and activator of transcription 3
  • Crohn’s disease
  • ulcerative colitis

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  • Published online first 8 May 2006

  • * K Mitsuyama and S Matsumoto share senior authorship.

  • The present work was supported in part by a Grant-in-Aid from the Japanese Ministry of Education, Culture, and Science (14770262) and Ministry of Health and Welfare.

  • Conflict of interest: None declared.

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