Mayo Clinic research in mice finds new role for Interleukin-6

A Mayo Clinic investigation of Interleukin-6, a hormone inside cells often considered a “bad actor” of the immune system because of its association with inflammation injuries and malignant diseases, shows that it also plays a therapeutic role in mice: it protects brain cells.

Interleukin-6 — called IL-6 for short by researchers — may, in fact, be a “white knight” for mouse brain cells, or neurons, as brain cells also are called. These results, while early, may be promising for humans as well. The Mayo Clinic investigation is described in the Jan. 15 Journal of Neuroscience.

Clinical Importance

Every part of the brain is connected by neurons. Yet both the aging process and many diseases are a steady assault on neurons. Says Moses Rodriguez, M.D., principal investigator of the Mayo Clinic study, “One of the biggest challenges we face as a society is the eventual loss and degeneration of neurons from many causes, including many diseases — from Alzheimer’s disease to multiple sclerosis to Parkinson’s disease — and other sorts of injury. As our population gets older, this becomes an even bigger issue. So identifying any factor that protects neurons or promotes their survival is an important step toward improving health as we age.”

This protective response holds considerable therapeutic significance since scientists already know how to make IL-6 in the laboratory. It may, therefore, be an appealing candidate for researchers to refine into an easily administered drug — a “brain booster” pill that conserves mental functioning, for example.

If these early results hold up in further studies, IL-6 — or other similar pharmaceutical compounds — could potentially serve as a new treatment for a range of conditions that destroy neurons, from Alzheimer’s disease to multiple sclerosis. Says Dr. Rodriguez, “Every disease that is a degenerative disease of the nervous system could potentially be amenable to some kind of treatment with a growth factor like IL-6 because its goal is to keep neurons alive.”

The Experiment

To function in a cell, IL-6 has to bind in a specific place — called a “receptor site” — in a specific way. Dr. Rodriguez and colleagues were intrigued that IL-6 uses the same receptor site used by compounds whose job is to promote neuronal survival. “To me, that was pretty wild,” Dr. Rodriguez says. “So I hypothesized that maybe this IL-6 is also playing a role in protecting neurons.”

Testing this idea required extensive genetic work to produce different mouse groups that varied in their ability to produce IL-6. All were infected with a virus that causes a degenerative nerve disease. Animals with the IL-6 gene got mildly sick, but did not die. Mice lacking the IL-6 gene got severely sick and started dying. Why?

To find a cause of death, the Mayo Clinic team analyzed the animals’ tissues. Their findings: neurons in the spinal cords of mice lacking IL-6 were degenerating dramatically. This evidence supported their hypothesis of a neuron-protection role for IL-6. It also led them to their next question: Where is IL-6 made?

An analysis of the brains of healthy mice possessing the IL-6 gene surprised them. “You look for IL-6 in the brain of a normal, healthy animal, and there is no IL-6 in a normal healthy animal!” Dr. Rodriguez says. “So then we infected the animals with the virus. Now when we looked for IL-6, guess what? It was everywhere.”

Specifically, IL-6 was found in astrocytes. Astrocytes are the supporting structures on the outside of neurons that help them connect to transmit nerve signals. Says Dr. Rodriguez, “As soon as you put this virus in, all those astrocytes — like a lightbulb — go on to make IL-6.” Their data show that of infected mice possessing IL-6, only two of 23 (~9 percent) died. By comparison, 17 of 29 mice (~60 percent) lacking IL-6 died after virus infection.

Intriguing Implications … Scientific Basis for Mind-Body Connection in Health

Since its discovery several decades ago, IL-6 has been called a “cytokine.” A cytokine is a substance secreted by the immune system. It plays a key role in regulating cells that do the work of the immune system, which is to defend the body from infection and injury.

While IL-6 is unquestionably a cytokine and as such, a proper “citizen” of the immune system, this new Mayo Clinic finding suggests a more complex identity of IL-6. Given its production in astrocytes, it seems IL-6 holds “dual citizenship” by also working in the realm of the brain to protect against neuronal injury. It is this intersection of mind-body systems that Dr. Rodriguez finds most intriguing.

“There is so much that we don’t know about immune-neural interactions that are really important,” he says. “For example, I’m a physician and I see a lot of patients. And I know that patients who take care of their bodies are helping their immune systems. I could believe that after we do the right kinds of things for our bodies — exercise, eat right, rest — we feel better and we think better because we are activating the right immune systems and because immune factors are acting in our brains. So it doesn’t surprise me that we are now finding that there may be immune factors that are actually very beneficial for neurons. We just didn’t know what they were before.”

He notes that this intersection of the immune and neuronal systems of the brain fits with many traditional and ancient healing practices that accept a mind-body connection as a foundation of health. “Maybe there’s a whole scientific basis for it all, and this finding is part of it,” Dr. Rodriguez says.

The Next Step

The Mayo Clinic researchers will continue to investigate the receptors for IL-6 in animal models and do other experimental work that could lead to clinical trials in humans. But Dr. Rodriguez cautions that this step is many years away. Much basic science remains to be done.

###
Lisa Copeland
507-284-5005 (days)
507-284-2511(evenings)
email: newsbureau@mayo.edu