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Cambridge University Science Magazine
Inflammation – it can save your life, or it can kill you. The process is necessary for the body’s response to injury and infection, where it helps to repair damaged tissue and fight off invading microbes. The problems start when levels of inflammatory mediators rise throughout the body in the absence of infections or tissue damage. This is known as ‘chronic low-grade systemic inflammation’, and has been implicated in many diseases, including cardiovascular disease, type 2 diabetes and even colon and breast cancers.

What can we do to stop it? Surely we need some sort of anti-inflammatory drug or medical intervention?

Perhaps not. We might be able to help ourselves more than we think by getting fit! It has long been known that exercise is good for the mind: it stimulates the release of endorphins, which give the athlete an allround feeling of positivity. However, it now seems that the benefits of exercise stretch far beyond that initial endorphin high, to include powerful anti-inflammatory effects. For example, studies have linked regular exercise with a reduction in circulating levels of C-reactive protein, a key marker of inflammation, within the blood.

To unlock the secret of how exercise fights inflammation, we have to go right down to the molecular level and think about cell signalling. In this process, proteins sequentially activate or inactivate each other to allow cells to communicate with their neighbours - as a person might pass a note to their friend - and to respond to changes in their environment with great precision. Cell signalling is the molecular mechanics of how we function, and when it goes wrong, we get ill.

Tiny messenger proteins called cytokines are key players in these delicately balanced, intricate biological networks. There are proinflammatory cytokines, such as tumour necrosis factor alpha (TNFα), which activate immune cells, promote cell death and induce fever. There are also anti-inflammatory cytokines, for example interleukin 10 (IL-10), which suppress inflammation by switching off pro-inflammatory molecules. When fatty tissue is laid down in the body, it also triggers the release of pro-inflammatory cytokines. This means that simply burning off fat through exercise can lower the level of these inflammatory mediators in the tissue.

To make things even more complicated, some cytokines can be either proinflammatory or anti-inflammatory, depending on their context. One such cytokine is interleukin-6 (IL-6), which appears to provide the missing link between exercise and inflammation. In an inflammatory environment, such as during an infection, immune cells produce large amounts of proinflammatory cytokines. These then stimulate the production of other cytokines, including IL-6, to recruit more immune cells and drive the rest of the inflammatory response. During exercise, however, IL-6 is the first cytokine released in huge quantities directly from the working muscle cells. The amount of IL-6 produced is proportional to the intensity and duration of the workout, and is higher in older people than younger people (so it really is never too late to get fit!).

Remarkably, the IL-6 released by exercising muscle cells does not promote the huge inflammatory response that the immune cell-cytokines evoke. Instead, it increases anti-inflammatory cytokine production, and even inhibits the king of the inflammatory cytokines, TNFα. This was demonstrated in a 2003 study, in which Bente Pedersen and colleagues simulated low levels of inflammation by injecting healthy volunteers with a toxin from the bacterium E. coli. They found that those who had been resting prior to injection experienced a 3-fold increase in TNFα levels in their blood. By contrast, those who had been exercising before toxin injection had no increase in the inflammatory cytokine, which suggests that exercise was able to quench the inflammatory response.

However, IL-6 isn’t the only mechanism that can take credit for the anti-inflammatory response to exercise. Both the motor sensors in the brain that detect physical movement and the IL-6 produced by muscle cells stimulate the adrenal glands to release the hormone cortisol into the bloodstream. Cortisol inhibits the production of pro-inflammatory cytokines by immune cells and thereby prevents the inflammatory response.

In addition, exercise doesn’t just change which signalling molecules immune cells produce; it also alters their movement and abundance in the blood. The lowgrade chronic inflammation observed in fatty tissue is largely due to immune cells called macrophages. These cells are guided to the fat by a trail of signalling proteins known as chemokines. It is thought that exercise promotes the general production of chemokines from multiple locations, which makes the trail ‘fuzzy’ and more difficult for the macrophages to follow.

Finally, exercise also alters the proportions of different types of immune cells within the blood. It reduces the number of proinflammatory cells, such as macrophages, and increases the number of regulatory T-cells, which keep the macrophages in check by suppressing their activity.

"... a study of patients suffering from coronary heart disease showed that exercise led to a decrease in mortality"

So how important is this anti-inflammatory response? Would exercise make a difference to diseases where inflammation is involved in onset and development? Can it really be used as a medicine for the body and not just the mind? It looks like it can. For instance, a study of patients suffering from coronary heart disease showed that exercise led to a decrease in mortality. Other trials have found that more physical activity protects people with impaired glucose tolerance from developing type 2 diabetes, to which they are predisposed. For those who have already developed the disease, exercise is used as a treatment (in combination with dietary changes and medication), where it lowers the risk of complications.

Before you are tempted to fly off into workout mode, hitting the gym for four hours a day in the hope that this will protect you from ever suffering from disease, it’s important to remember that the key is balance. Firstly, it is possible to do too much: excessive exercise can pushes the anti-inflammatory response so far that it can lead to immunosuppression. That is why elite athletes who endure lengthy intense training are more susceptible to upperrespiratory tract infections than people who do absolutely no exercise. Secondly, exercising doesn’t guarantee you a disease-free life. It’s just one of those little steps that you can take to increase your overall health and reduce your risk of disease. So jump on that treadmill or into the pool, take the time to re-connect with your favourite activity or sport, and keep your mind and body happy and healthy.

Image credit: Richard Beatson