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.

Keywords: fibrosis; inflammation; therapeutics.

Figure 1.. Overview of the evolution in our understanding of IL11 (patho)biology from its discovery in 1990 to present day.

IL11 was initially thought important for haematopoiesis and a cytoprotective factor based mostly on experimental data generated using rhIL11 in mice. The conviction of its therapeutic properties led to a number of clinical trials in patients and it remains used to this day to treat thrombocytopenia. In 2017, IL11 was found to be toxic and subsequent proof-of-concept therapeutic studies across a range of mouse models of fibro-inflammatory diseases have led to clinical trials of anti-IL11 therapies.

Figure 2.. IL11-activated signalling, cellular mesenchymal transitions and organ-level pathologies.

IL11 is not detected in health but is up-regulated, as an alarmin-like response to toxic, genetic, infective, mechanical, oxidative or metabolic disease factors. IL11 signalling pathways converge to cause mesenchymal transitions and a pro-inflammatory state across cell types. This leads to stromal inflammation, fibrosis, loss of specialised cellular functions, failed endogenous repair mechanisms and organ failure. Red connectors: inhibitory effects.

Figure 3.. 1999–2023, how our understanding of the role of IL11 in liver disease changed.

Initial studies taught that IL11 is protective against immune-related hepatitis [40], APAP-induced liver failure [35,37], CCl₄-induced liver damage [148] and ischaemia-reperfusion injury [39] that catalysed a clinical trial of rhIL11 as a treatment for patients with hepatitis C [59]. Later studies found instead that endogenous IL11 is hepatotoxic and that anti-IL11 therapy can be used to treat NASH and APAP-induced liver failure [21,61], IL11:IL11RA:gp130 signalling prevents liver regeneration [62,109], IL11 is a therapeutic target in alcoholic liver disease [107] and that siRNA against Il11 or Il11ra1 treats NASH and CCl₄ liver toxicities [95,96].