Researchers at Duke-National University of Singapore (Duke-NUS) Medical School have discovered for the first time that interleukin-11 (IL-11) may be an important therapeutic target for cardiovascular (CV) fibrotic diseases, including heart and renal failure, they reported in the Nov. 13, 2017, edition of Nature.

A multifunctional cytokine, IL-11 was first isolated from bone marrow-derived stromal cells in 1990 and initially thought to be a key regulator of hematopoiesis, which has subsequently been disproved.

Fibrosis with collagen formation is a final common pathology in CV disease, causing mechanical and electrical dysfunction in the heart and being predictive of the onset of renal failure.

"Physiologically, collagen is required as a scaffold to support normal tissues, but in excess it forms scar tissue detrimental to organ function," study leader Stuart A Cook, Tanoto Foundation professor of cardiovascular medicine at Duke-NUS Medical School and a senior consultant at the National Heart Centre Singapore, told BioWorld.

"This is the first study to show that IL-11 is crucial in the pathogenesis of CV fibrosis and overturns a misconception existing in the literature," said Cook, adding that "there are currently no specific treatments for CV fibrosis, which represents an unmet clinical need."

Transforming growth factor beta1 (TGFB1) is known to be the main profibrotic factor, but its inhibition is associated with multiple side effects, due to TGFB1 itself playing important pleiotropic roles, whereby one gene influences seemingly unrelated phenotypic events.

Cook and his team therefore hypothesized that downstream effectors of TGFB1 in fibroblasts might represent attractive therapeutic targets lacking the upstream toxicities associated with directly targeting TGFB1.

Using an integrated imaging-genomics target discovery platform based on primary human fibroblasts, the researchers demonstrated that up-regulation of the IL-11 gene was the dominant transcriptional response to TGFB1 exposure and was required for its effects.

"We developed a new target-discovery platform that integrates genomic data derived from RNA sequencing with high-throughput imaging analysis of the cellular features of fibrosis in primary human fibroblasts cultured from biopsies donated by patients undergoing cardiac surgery," explained Cook.

The researchers further showed that IL-11 and its receptor IL-11RA were expressed specifically in fibroblasts, where they drive the intracellular signaling pathway responsible for fibrogenic protein synthesis.

They also demonstrated in mice that fibroblast-specific IL-11 transgene expression or the injection of IL-11 caused heart and kidney fibrosis and eventual organ failure, whereas genetic deletion of IL-11RA was protective against disease.

"Using genomic engineering techniques, we created normal laboratory mice in which IL-11 in fibroblasts could be turned on when required," said Cook. "When IL-11 was injected into these mice in separate experiments, their hearts and kidneys became fibrotic and failed within just two weeks."

However, "in genetically-engineered mice in which IL-11RA had been deleted, when they were stimulated to develop heart or kidney disease as preclinical models of disease, these animals were found to be protected against fibrosis," he added.

Inhibition of IL-11 therefore prevents fibroblast activation across both organs and species, in response to various pro-fibrotic stimuli, revealing the central role played by IL-11 in fibrosis.

Those findings suggest IL-11 inhibition could be an important new therapeutic strategy for the treatment of fibrotic diseases, which is further supported by robust target safety data.

"We are now developing drugs that we hope can be used to prevent, arrest or even reverse fibrosis of the heart and kidney, which may lead to new ways of preventing diseases including atrial fibrillation, and heart and kidney failure, the incidence of both of which is reaching epidemic proportions," said Cook.

"Fibroblasts are present in all of the body's organs and we are now investigating the effect of IL-11 on the fibroblasts in these organs," he noted. "We are also currently investigating how antibody therapy might prevent heart and kidney fibrosis in preclinical models."