RT Journal Article
SR Electronic
T1 Interleukin 11 expression causes murine inflammatory bowel disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 756098
DO 10.1101/756098
A1 Wei-Wen Lim
A1 Benjamin Ng
A1 Anissa Widjaja
A1 Chen Xie
A1 Liping Su
A1 Nicole Ko
A1 Sze-Yun Lim
A1 Xiu-Yi Kwek
A1 Stella Lim
A1 Stuart A Cook
A1 Sebastian Schafer
YR 2019
UL http://biorxiv.org/content/early/2019/09/05/756098.abstract
AB 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 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.