Transgenic interleukin 11 expression causes cross-tissue fibro-inflammation and an inflammatory bowel phenotype in mice
Autoři:
Wei-Wen Lim aff001; Benjamin Ng aff001; Anissa Widjaja aff002; Chen Xie aff001; Liping Su aff001; Nicole Ko aff002; Sze-Yun Lim aff001; Xiu-Yi Kwek aff001; Stella Lim aff002; Stuart Alexander Cook aff001; Sebastian Schafer aff001
Působiště autorů:
National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
aff001; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
aff002; National Heart and Lung Institute, Imperial College London, London, England, United Kingdom
aff003; MRC-London Institute of Medical Sciences, London, England, United Kingdom
aff004
Vyšlo v časopise:
PLoS ONE 15(1)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0227505
Souhrn
Interleukin 11 (IL11) is a profibrotic cytokine, secreted by myofibroblasts and damaged epithelial cells. Smooth muscle cells (SMCs) also secrete IL11 under pathological conditions and express the IL11 receptor. Here we examined the effects of SMC-specific, conditional expression of murine IL11 in a transgenic mouse (Il11SMC). Within days of transgene activation, Il11SMC mice developed loose stools and progressive bleeding and rectal prolapse, which was associated with a 65% mortality by two weeks. The bowel of Il11SMC mice was inflamed, fibrotic and had a thickened wall, which was accompanied by activation of ERK and STAT3. In other organs, including the heart, lung, liver, kidney and skin there was a phenotypic spectrum of fibro-inflammation, together with consistent ERK activation. To investigate further the importance of stromal-derived IL11 in the inflammatory bowel phenotype we used a second model with fibroblast-specific expression of IL11, the Il11Fib mouse. This additional model largely phenocopied the Il11SMC bowel phenotype. These data show that IL11 secretion from the stromal niche is sufficient to drive inflammatory bowel disease in mice. Given that IL11 expression in colonic stromal cells predicts anti-TNF therapy failure in patients with ulcerative colitis or Crohn’s disease, we suggest IL11 as a therapeutic target for inflammatory bowel disease.
Klíčová slova:
Collagens – Colon – Fibrosis – Histology – Inflammation – Inflammatory bowel disease – Kidneys – Mouse models
Zdroje
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