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
- signal transducer and activator of transcription 3
- Crohn’s disease
- ulcerative colitis
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