Interferons are a group of inflammatory molecules with a key role: to stimulate the capacity of the immune system to eliminate pathogens or to fight tumors.

Research published today in Immunity and coordinated by Renato Ostuni – group leader of the Genomics of the Innate Immune System Unit at the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) in Milan – describes the new role of a gene acting as a switch for the production of interferon β.

The discovery, which suggests a new therapeutic target to modulate the immune response, has important implications in the fight against infectious and oncological diseases and paves the way for the development of more effective gene therapy protocols.

 

The role of type I interferons

Type I interferons are among the most powerful inflammatory molecules. As such, these proteins are essential for our survival, but also potentially dangerous: if they are not produced adequately when needed, the immune system cannot successfully defend us against pathogens and tumors; if they are produced in excess or out of context, they can promote the onset of autoimmune and inflammatory diseases.

“That's why evolution has created a series of redundant safety switches: different genes that have to be activated in series before allowing interferons to be synthesized and released outside of the cell," explains Renato Ostuni. "It works as control and protection system, designed to prevent inflammatory molecules from being released into tissues when not strictly necessary.”

 

A new regulator of interferon β

Several genes involved in the regulation of interferons have already been discovered. Now, thanks to the new study published by Ostuni's research group, we know one more: its name is MEF2A and it encodes for a protein (or 'transcription factor') already known for its role in the development of the nervous and muscular systems. Until now, however, no one suspected that MEF2A could also play such a key role in the functioning of the immune system.

Researchers discovered MEF2A by studying a molecule – prostaglandin E2, or PGE2 – known for its ability to modulate immune responses. Normally, PGE2 prevents interferons from being released when not needed and therefore helps to keep tissues healthy. "PGE2 is also an essential ingredient in gene therapy protocols because it allows blood stem cells to be cultured and engineered while preserving their full functionality," Ostuni adds. "International studies even suggest that PGE2 may promote bone marrow regeneration after transplantation."

However, as it is often the case, cancer cells are capable of altering physiological mechanisms and use them to their advantage. Prostaglandin E2 is produced in large quantities by certain types of tumors, as a way of reducing inflammation and escaping the control of the immune system. “The downside of having so many control mechanisms for inflammatory molecules, such as interferons, is that the system is particularly vulnerable to the 'hacking' strategies of tumor cells: sometimes it is enough to turn off one gene to prevent the release of interferons and keep the immune system under control,” Ostuni explains.

 

Implications of the discovery

The discovery of a new gene regulating the production of interferon β and the ability of a molecule –prostaglandin E2 – to limit its function has multiple applications, ranging from the treatment of infectious diseases to the development of new immunotherapy strategies for tumors.

"Furthermore, it will allow us to improve gene therapy protocols: the regenerative capacity of blood stem cells is compromised by inflammatory phenomena, both during genetic correction procedures and following transplantation."

The group of researchers coordinated by Ostuni is already working to translate the results of this basic research – conducted using state-of-the-art technologies and bioinformatics analysis – into advanced cell therapies, the primary mission of the SR-Tiget institute. "Interferon β has a key role in regulating immune responses in a variety of situations. Knowing how to better control its production opens up exciting perspectives that we can't wait to explore" concludes Renato Ostuni.