Interleukin-6 (IL-6) is a well-known cytokine, a protein that plays a crucial role in the human immune system by regulating inflammation, for example in response to a bacterial infection. IL-6 has also been linked to a variety of diseases such as rheumatoid arthritis, and is an important component of the cytokine storm caused by severe cases of COVID-19.

In a new study published in the journal Stem Cell Reports today, researchers at the Centre for Genomic Regulation (CRG) in Barcelona have found that IL-6 also plays a role in the development of mammalian embryos. The findings are surprising because it is the first time IL-6 has been shown to facilitate the early stages of life and without involving a response to a pathogen.

The researchers had previously been studying the mechanisms by which a protein known as C/EBPa helps transform differentiated cells into pluripotent stem cells. They found this process required IL-6 and that C/EBPa regulated the genetic expression of the cytokine. The authors speculated that their observations reflect a function of IL-6 and C/EBPa when pluripotent stem cells are formed – during early embryonic development.

A team led by Dr. Thomas Graf, Group Leader at the CRG, made the discovery by studying how two tissues form at the earliest stages of development in mouse embryos. One tissue, the trophectoderm, consists of cells that comprise the outer layer of the embryo and will eventually give rise to the placenta. The other is the inner cell mass, a group of cells that will eventually transform into the main structures of the embryo.

Studying the genes that these two tissues express, the team found that both C/EBPa and its downstream target gene IL-6 are expressed in the trophectoderm, while the receptor for the IL-6 protein is expressed in the inner cell mass. This suggested that IL6 is secreted by trophectoderm cells and activate the receptors in the inner cell mass, a hypothesis confirmed by further experiments.

Importantly they were then able to show that reducing levels of IL-6 impaired the formation of blastocysts, suggesting that the trophectoderm acts as a niche for embryonic stem cells in the inner cell mass. The authors of the study compare the relationship to how stromal cells in the bone marrow enable the formation of blood stem cells.

“We knew that early embryonic tissues have ‘conversations’ with each other because previous studies have shown that soluble factors produced by the inner cell mass facilitate the development of the trophectoderm. What’s novel here is the discovery of a direct mechanism that enables this cross-talk in the opposite direction. That it involves a cytokine best known for its properties in inflammation in adult life makes this discovery even more surprising,” says Dr. Graf.

Although the experiments described in this study with mouse embryos cannot be performed with human embryos for ethical reasons, the finding of a similar expression pattern of IL-6 and its receptor suggests that a similar mechanism also operates in humans.

Asked about the next steps of the laboratory Marcos Plana, first author of the study, explains: “Our data showing that C/EBPa activates the expression of the trophectoderm gene IL6 raise the possibility that it also regulates other trophectoderm restricted genes and perhaps is a driver of trophectoderm development. The new study illustrates that more mysteries remain to be solved around the earliest events in our lives.”

Imagen: IL-6 binds to the inner cell mass of a blastocyst. Left: brightfied image; Right: the same blastocyst with nuclei of cells visualized in blue and IL6 binding in red. The stippled line shows the position of the inner cell mass representing the future embryo, surrounded by the trophectoderm. Credit: Marcos Plana/CRG

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