Understanding interleukin 11 as a disease gene and therapeutic target.

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.