Transgenic interleukin 11 expression causes cross-tissue fibro-inflammation and an inflammatory bowel phenotype in mice

Abstract

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 (Il11 SMC). Within days of transgene activation, Il11 SMC mice developed loose stools and progressive bleeding and rectal prolapse, which was associated with a 65% mortality by two weeks. The bowel of Il11 SMC 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 Il11 Fib mouse. This additional model largely phenocopied the Il11 SMC 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.

Fibroblast‐specific IL11 signaling drives chronic inflammation in murine fibrotic lung disease

“…After 5 days of tamoxifen treatment, there was a ~56% reduction in IL11RA protein levels in whole lung lysates from CKO mice, which is expected given the predominant expression of Il11ra1 in Col1a2 +ve fibroblasts ( Figure 1B and S2B). 19,20 Immunofluorescence staining revealed a greatly decreased expression of IL11RA ( Figure 1C) and we detected a ~70% reduction of Il11ra1 mRNA expression in primary fibroblasts isolated from the lungs of CKO mice when compared to control mice ( Figure 1D). Confirming fibroblast-specific deletion, tamoxifen treatment did not affect the expression of Il11ra1 in a Col1a2 -ve cell type from the lungs of CKO mice.…”

Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models

“…To study the effects of IL11 on VSMCs in vivo, we crossed Rosa26 Il11/ + transgenic mice 14 with mice that express tamoxifen (TAM)-inducible Cre recombinase driven by the myosin heavy chain 11 ( Myh11 ) promoter 29 . This model allows SMC-specific Il11 overexpression in an inducible manner in adult mice (referred to here as Il11 -Tg mice) 30 .…”

Different roles of interleukin 6 and interleukin 11 in the liver: implications for therapy

“…23 While we know much less about IL11, it has emerged as an important pro-fibrotic factor across organs and, more recently, as a hepatotoxin. 5,[8][9][10][11] IL6R and IL11RA expression in hepatocytes and hepatic stellate cells IL6, originally termed B cell growth/stimulatory factor II (BSF2), 24 was initially shown to stimulate acute phase response from HepG2 cells and rat hepatocytes. 25 Subsequent studies showed that IL6 can be produced from and act on the liver and IL6 is a well-established and important determinant of the acute phase response, which involves secretion of CRP, serum amyloid A, hepcidin, among other factors from hepatocytes.…”

“…7 Only very recently, have experiments shown a central role for endogenous and species-matched IL11 in the pathology of fibroinflammatory diseases such as inflammatory bowel disease (IBD), cardiorenal and lung fibrosis, and acute and chronic liver disease. 5,[8][9][10][11] In this review, we examine the roles IL6 and IL11 in the liver and discuss the therapeutic opportunities these cytokines may provide for liver disease. While the older literature proposed these two cytokines have overlapping and redundant roles in the liver, we discuss recent data that challenges longheld assumptions.…”