STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice. Issue 9 (8th May 2006)

• Record Type: Journal Article
• Authors: Mitsuyama, K; Matsumoto, S; Rose-John, S; Suzuki, A; Hara, T; Tomiyasu, N; Handa, K; Tsuruta, O; Funabashi, H; Scheller, J; Toyonaga, A; Sata, M
• Is Part Of: Gut. Volume 55:Issue 9(2006)
• Page Start: 1263
• Page End: 1269
• Publication Date: 2006-05-08
• Subjects: 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; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2005.079343
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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.