Understanding interleukin 11 as a disease gene and therapeutic target

Abstract

Interleukin 11 (IL11) is an elusive member of the IL6 family of cytokines. While initially thought to be a haematopoietic and cytoprotective factor, more recent data show instead that IL11 is redundant for haematopoiesis and toxic. In this review, the reasons that led to the original misunderstandings of IL11 biology, which are now understandable, are explained with particular attention on the use of recombinant human IL11 in mice and humans. Following tissue injury, as part of an evolutionary ancient homeostatic response, IL11 is secreted from damaged mammalian cells to signal via JAK/STAT3, ERK/P90RSK, LKB1/mTOR and GSK3β/SNAI1 in autocrine and paracrine. This activates a program of mesenchymal transition of epithelial, stromal, and endothelial cells to cause inflammation, fibrosis, and stalled endogenous tissue repair, leading to organ failure. The role of IL11 signalling in cell- and organ-specific pathobiology is described, the large unknowns about IL11 biology are discussed and the promise of targeting IL11 signalling as a therapeutic approach is reviewed.

Inhibiting the Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Cascade in Cancer and the Heart: for Better or Worse, in Sickness and Health?

“…Furthermore, cardiomyocyte-specific deletion of BRAF inhibits cardiomyocyte hypertrophy and interstitial fibrosis in a mouse model of hypertension [73]. The latter observation is consistent with studies of IL11 that illustrate the importance of cardiomyocyte ERK1/2 signalling in the fibrotic response [76][77][78].…”

“…For example, microRNA-21 activates ERK1/2 signalling in cardiac fibroblasts by downregulation of an endogenous inhibitor of the pathway, Spry1, and promotes fibroblast survival along with interstitial fibrosis in the heart [75]. Moreover, recent studies of interleukin 11 (IL11) highlight the role of ERK1/2 signalling in the interplay between cardiomyocytes and cardiac fibroblasts to increase fibrosis in the heart [76][77][78].…”

Identification of Serum Biomarkers to Monitor Therapeutic Response in Intestinal-Type Gastric Cancer

“…Here, we have utilized an animal model of IGC to identify potential blood-based biomarkers unique to disease stage, in addition to biomarkers that may predict tumor regression, with a focus on therapeutic inhibition of IL-11 signaling. These studies are timely, as monoclonal antibodies targeting IL-11 or its receptor have entered Phase I/II clinical trials [ 24 ].…”

Platelet-Rich Fibrin Increases CXCL8 Expression in Gingival Fibroblasts

“…In this context, we have identified PRF as causing a robust increase in IL11 [ 15 ] expression in gingival fibroblasts, an effect that can be traced back to the activation of TGF-β signaling provoked by PRF. IL11, in turn, is a potent pleiotropic cytokine that drives the gp130—IL6-family signaling pathway in various cell types with a prominent role in tissue homeostasis, including bone [ 30 ], also causing pathological changes related to fibrosis [ 31 ]. Our present goal is to identify further genes targeted by PRF that may be linked to the autocrine and paracrine activity of gingival fibroblasts, which is, in the present study, CXCL8.…”