The Body on Fire

The immune system is supposed to be our great defender, the army that protects us against invading pathogens and rebuilds tissues damaged by injury. One of its master tactics is inflammation, where the body floods an injured or infected site with plasma and white blood cells, causing the familiar swelling, redness and don’t-touch-me-there tenderness. Without it, wounds would never heal, and germs would win the war.

But sometimes the inflammation-signaling cells that are supposed to fall back at the end of their mission keep fighting, attacking an enemy only they can perceive. What keeps the battle going? Recurring irritants, such as cigarette smoke, for one. Or, as we now know, carrying too much extra weight, or simply getting older.

It doesn’t mean your insides swell and throb the way your toe does when you stub it. Chronic, low-grade inflammation is not the kind you can feel, or even something you can see under a microscope. Instead, inflammatory molecules circulate at such low levels that only very sensitive tests can detect them.

A full-blown infection, for example, might shoot your blood levels of C-reactive protein (CRP), a molecule released by the liver as part of the immune response, from 0 milligrams per liter up to 1,000 mg/L. Chronic inflammation, on the other hand, might register a benign-looking 3 mg/L.

“It’s very subtle,” says Professor Joel Mason, director of the Vitamins and Carcinogenesis Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts. “It’s inflammation on a biochemical level.”

But even at such a slow burn, this silent war takes a toll on the body. A CRP level of 3mg/L is enough to triple your risk of heart disease. In fact, chronic inflammation is connected to many of the illnesses we see more often as we age.

“Inflammation is thought to be an important basis not just for cancer, but for insulin resistance and diabetes and atherosclerotic disease and any number of other conditions,” Mason says. “There is a lot of research going on into what role inflammation plays in a lot of the chronic degenerative diseases that our society falls prey to.”

If inflammation is the common denominator, then finding a way to dampen it through nutrition could have far-reaching health consequences. (See the related story, “The Search for Foods that Soothe.”) Research already suggests that inflammatory cooling properties may be what makes the fish-and-oil-rich Mediterranean diet effective in preventing cardiovascular disease and explain part of the heart-healthy power of oats. Eating fruits and vegetables, which we already know decreases the risk of cancer, may work by blocking inflammation.

Professor José Ordovas, who directs the Nutrition and Genomics Laboratory at the HNRCA, cochairs a cluster of researchers throughout the center who are looking at how inflammation leads to disease and how what we eat may tamp it down. Scientists have been making steady progress, he says, by studying the inflammation that underlies many diseases, rather than concentrating solely on individual illnesses.

“What happens sometimes is that we focus on the branches, because they are easy to work with, and we don’t dig to reach the origin or the roots of the problem,” he says.

The Obesity Connection

It seems like the ultimate betrayal—the immune system that is supposed to defend us ends up attacking us. “The inflammatory response, in part, was put there to help us respond to various bodily insults, whether that insult is an infection or wound,” Mason says.

But many people have come to live in a way—overstuffed and sedentary—that they weren’t meant to live. “Man wasn’t obese as he was evolving over tens of millions of years,” Mason argues. “And I don’t think our body was designed to have this sustained inflammatory response that would persist for months and years, as it does apparently in obesity.”

Everyone knows that weight gain and diabetes are closely linked. It is only more recently that researchers have seen how inflammation may be one of the bridges that connect them.

“With obesity, there is a release of fatty acids and other factors that fuel inflammation and insulin resistance,” says Atkins Professor in Metabolism and Nutrition Andrew Greenberg, director of the HNRCA’s Obesity and Metabolism Laboratory.

For a long time, scientists thought that the extra fat we carry on our bodies was fairly inert stuff—just more baggage to slow us down. But more recent studies, including groundbreaking research by Greenberg, have shown that fat is actually a hormonal powerhouse. As people gain weight, their fat cells grow larger.

When that happens, the cells churn out several inflammation-inducing proteins, known as cytokines. And they do it at a surprising rate. One of these cytokines is Interleukin-6. You usually find IL-6 when the body’s immune system is doing its day job, fighting an infection or trying to heal a burn, for example.

But one study found that obese people had 10 times as much IL-6 in their fat tissue as normal-weight people. IL-6 and other inflammatory factors “block insulin’s ability to signal in the cell,” Greenberg explains, which is one way insulin resistance, the precursor to diabetes, can develop. This increase in inflammation appears to be a necessary step on the path to diabetes.

Enlarged fat cells bring on inflammation for a number of reasons. They release fatty acids into the blood, which seem to spur an inflammatory response. People who carry a lot of weight also tend to have high numbers of macrophages in their fat. Macrophages are immune system weapons that normally gobble up pathogens or dead cells.

Researchers believe the body sends the macrophages to clean up dead fat cells, the numbers of which increase dramatically with obesity. Once there, the macrophages infiltrate the fat and start sending out pro-inflammatory signals. In laboratory studies, obese mice that had excess macrophages started making a lot more insulin, and eventually developed insulin resistance.

Gateway to Cancer

Inflammation might also explain, in part, the connection between being fat and getting cancer. Scientists have long known that if you carry extra weight, you are more likely to get cancer. And you don’t need to be obese.

“Being obese increases your risk of developing colon cancer by two- or threefold,” says Mason, who has done numerous studies on colon cancer. “But just being overweight increases your risk by 20 percent.”

Now scientists suspect that it is the inflammation brought on by obesity that contributes to that risk. Certain cancers have a direct connection to inflammation. Cigarette smoking, for example, irritates the lungs, which leads to inflammation and lung cancer. The human papillomavirus causes a chronic infection, and the subsequent inflammation leads to cervical cancer. And people with chronic inflammatory bowel disease have a five- to sevenfold increase in their risk for developing colon cancer.

But obesity in and of itself seems to promote cancer. Take liver cancer. The number of cases of liver cancer in the United States has doubled in the past 25 years, although researchers are unsure why. The usual causes—excessive alcohol use and viruses such as hepatitis B and C—have not increased. One thing has, though: obesity.

When a person gets fatter, so does his liver, and that fat infiltration can cause the liver to become inflamed. In laboratory studies of rats that were given a small amount of a liver-specific carcinogen, obese rats showed more inflammation markers and more precancerous lesions in their livers than regular-weight rats, says Professor Xiang-Dong Wang, N92, director of the HNRCA’s Nutrition and Cancer Biology Laboratory, which performed the experiments.

How does it happen? Joel Mason has discovered one route by which obesity-induced inflammation spurs cancer, at least in the colon. The lining of the colon is one of the most rapidly proliferating tissues in the body, producing tens of millions of new cells every day.

“About every four or five days, you have an entirely new lining in your colon,” Mason says. The destruction of old cells and the creation of new ones is orchestrated by cascades of intercellular signals. One of them, the Wnt signaling pathway, is integral to colon health. But when this pathway is overactivated, it can lead to the uncontrolled cell growth that is cancer. “More than 85 percent of all human colon cancers are thought to arise because of overactivation of this pathway,” Mason says.

What triggers the overactivation? The inflammation brought on by obesity, for one. In studying the colons of obese mice, Mason saw elevated levels of pro-inflammatory cytokines, lots of Wnt signaling and an accompanying increase in cellular proliferation.

Mason says he is not trying to argue that Wnt signaling is the sole way in which obesity increases the risk for colorectal cancer, but he does believe it could be a substantial, biologically plausible pathway.

“It takes a number of different pushes from different directions to finally get the ball rolling where cells just finally decide that they are going to become cancerous,” he says. “Some of us think that they get nudged a little bit by these pro-inflammatory cytokines.”

Another theory about how inflammation leads to cancer has to do with oxygen free radicals, molecules that the inflammatory response signals to kill such intruders as bacteria or viruses.

Unfortunately, these free radicals tend to destroy anything they come in contact with, including healthy cells. Sometimes a free radical damages a healthy cell just enough to mutate its DNA, which can trigger a cycle of abnormal cell growth.

Typically, cells have built-in mechanisms to prevent damaged DNA from being copied. But the inflammatory response, in its good-hearted attempt to promote the creation of healthy tissue after an injury, can work against those mechanisms—and even spur new blood supplies that help to fuel the growth of the abnormal cells.

It makes sense, then, that people who eat lots of fruits and vegetables have a lower risk of cancer; colorful produce is rich in carotenoids and other antioxidants, which neutralize free radicals.

But sorting out which antioxidants are actually dampening inflammation has been tricky. In studies of obese rats, Wang’s laboratory supplemented the rats’ diet with either lycopene—an antioxidant found in tomatoes—or tomato extract. Both helped dampen inflammation, but the tomato extract did a better job.

In this case, the purified compound was not as effective as the whole food. To Wang, this means people are better off eating more tomato sauce and leaving the lycopene supplements on the shelf. “You better get this protection from your diet,” he advises.

His lab is also looking at whether consuming certain nutrients can block the cancer-inducing inflammation caused by cigarette smoke. They started by looking at a Harvard analysis of dietary intake studies, which showed that smokers who ate foods rich in a carotenoid called beta-cryptoxanthan (found in pumpkin, sweet red peppers, papayas, oranges and carrots) had a lower incidence of lung cancer.

Wang’s lab took two groups of ferrets—one given beta-cryptoxanthan and one not—and exposed them to cigarette smoke. The animals that were given the supplement fared much better. “It almost totally blocked smoking-induced inflammation and precancerous lesions,” Wang says. A follow-up study went a step further: It found that beta-cryptoxanthan actually prevented the growth of lung tumors in animal lung cancer models. The research was presented at the American Association of Cancer Research annual meeting in April.

Heart Attack Trigger

Chronic inflammation gained its current notoriety when it was implicated in the number-one cause of death around the world: cardiovascular disease. The old, simplistic belief was that having a high concentration of cholesterol in the blood would cause it to build up in blood vessel walls until it decreased or totally blocked the flow of blood—a clog in the plumbing, so to say.

Now researchers theorize that there is more to the relationship between blood cholesterol and arterial cholesterol, and that inflammation plays an important role in promoting these blockages, or plaques, as well as in triggering chest pain, stroke and heart attack.

The process works something like this. High concentrations of LDL, the “bad” cholesterol, lodge in the lining of blood vessels. Macrophages, those scavenger cells sent out by the immune system, recognize that the LDL isn’t supposed to be there, and ingest it. These cells, now puffed with cholesterol, embed themselves in the blood vessels and form the fatty streaks that are the first step in plaque formation.

Inflammatory signals sent out by the macrophages encourage additional cholesterol buildup. Eventually, a fibrous collagen cap develops and seals off the plaque. These capped plaques can sit benignly for years. Only when the plaques rupture does trouble begin, and again inflammation seems to be the culprit. In laboratory tests, researchers have seen that macrophages can secrete enzymes that degrade the cap.

“Inflammation is thought to make atherosclerotic lesions less stable,” explains Gershoff Professor Alice H. Lichtenstein, director of the HNRCA Cardiovascular Nutrition Laboratory. “If they rupture, the surface becomes thrombogenic, making it more likely a blot clot will form and clog up a vessel.” If the clot blocks the flow of blood to the heart, you have a heart attack. To the brain, you have a stroke.

Simply getting older can also increase chronic inflammation.

“Age-associated inflammation has been identified as an important contributor to many of the age-associated diseases, including Alzheimer’s, osteoporosis, loss of muscle mass and infection, in addition to cancer and cardiovascular disease,” says Simin Nikbin Meydani, director of the HNRCA and its Nutritional Immunology Laboratory, who has worked on several studies looking at age-related inflammation over the past 25 years.

She has found that one of the important players in the aging game is a messenger chemical, prostaglandin E2, which normally helps activate the inflammatory response. As we age, our bodies tend to make more prostaglandin E2, and that excess has been associated with nerve pain, plaque rupture in the arteries, cancer and suppression of function in T cells, which are crucial to the immune system.

COX-2 inhibitors, a group of anti-inflammatory drugs, can suppress prostaglandin production, but they can cause dangerous side effects such as stomach bleeding. So Meydani and her HNRCA colleague, Assistant Professor Dayong Wu, have been looking at foods or supplements that might do the same job as the drugs. For example, people who eat diets high in omega-3-rich fish produce less prostaglandin. Vitamin E was shown both in mice and humans to reduce prostaglandin E2 production and improve immune response. Studies also showed that restricting calorie intake lowers prostaglandin production while improving immune response.

So what can you do to keep inflammation at bay? The best defense may be keeping body fat in check. Weight loss has been shown to decrease people’s levels of C-reactive protein, one of the markers of inflammation. A 2002 study in the journal Circulation tracked 25 obese, postmenopausal women who went on a weight-loss diet. They lost an average of 30 pounds, and reduced their CRP more than 30 percent.

Then again, most Americans haven’t exactly excelled at keeping their bodies at a healthy weight. That’s why Greenberg, Mason and others have been looking at other ways to interrupt the obesity-inflammation-disease cycle.

“We have identified various factors, which, if we block their action, blocks inflammation and promotes improved insulin and glucose blood levels in obese animals,” Greenberg says. The next step will be identifying drugs—or nutrients—that can curb the inflammation and reduce the rate of obesity-associated diabetes, which is reaching epidemic proportions.

This story first appeared in the Summer 2012 Tufts Nutrition magazine.

Julie Flaherty can be reached at julie.flaherty@tufts.edu.