The Other Side of Cytokines

by Scott P. Edwards

September, 2006

Cytokines, small proteins released by cells throughout the body, are generally known as chemical messengers that play a critical role in controlling inflammatory and immune responses. Growing evidence suggests, however, that cytokines also contribute to neuropathology, including disease effects on brain signaling and neural circuit behavior.

Among the different types of cytokines (interleukins, interferons, and chemokines, among others), researchers have found that one class—proinflammatory cytokines—are involved in what is known as the “sickness response.”

Immune System and Brain

The sickness response is a nonspecific immune reaction that triggers a series of physiological and behavioral changes, including fever, eating and drinking less, decreased social interaction, and increased anxiety. It also activates the body’s stress response. Triggered by signals in the brain’s hypothalamus, the sickness response is the body’s attempt to produce energy to fight infection as well as preserve energy through behavior changes.

Scientists have found that macrophages, cells that protect the body against infection, create proinflammatory cytokines including interleukin-1, interleukin-6, and tumor necrosis factor. These work inside the brain to activate the sickness response.

“This name [proinflammatory cytokines] reflects the fact that these proteins orchestrate and augment inflammatory responses,” says Linda R. Watkins of the Center for Neuroscience at the University of Colorado at Boulder. Preventing their actions blocks sickness, whereas administering them can lead to a sickness response, she adds.

Watkins and her colleague at the University of Colorado, Steven Maier, found that cytokines produced in the blood by macrophages (a type of white blood cell that helps to destroy bacteria) are not what tell your brain that you are sick, primarily because they are too large to pass through the blood-brain barrier, the tight layer of cells and tissue that normally keeps immune cells from entering the brain. Rather, the cytokines’ message passes through the vagus nerve to the brain.

Along the vagus nerve, which extends from the brainstem to the abdomen, sit small pockets of cells called paraganglia that secrete neuro­transmitters. The paraganglia have receptors for interleukin-1 (IL-1), one of the proinflammatory cytokines released by macrophages.

Maier first described the immune-to-brain circuit that regulates the sickness response in 2001. A macrophage releases IL-1, which binds to paraganglia along the vagus nerve, he said. Neurotransmitters in the paraganglia then activate the vagus nerve, sending the signal to the brain. This signal in turn tells the brain to make its own IL-1, which sets off the sickness response and sends the signal back to the immune system.

The Paradoxical Effects of TNF-alpha

As a key regulator of the immune response, tumor necrosis factor-alpha (TNF-alpha) is a typical proinflammatory cytokine. In the central nervous system, TNF-alpha affects temperature regulation and the hypothalamic-
pituitary-adrenal axis, a major part of the neuroendocrine system, which controls reactions to stress.

But, says Harris A. Gelbard, a neuro­logist at the University of Rochester Medical Center, the role of TNF-alpha is paradoxical: it has both a protective and an inflammatory function in the brain. Many factors can influence whether TNF-alpha will have a protective or toxic effect on neurons, he says.

TNF-alpha plays a critical role in normal brain development, Gelbard says. It modulates the entire spectrum of neuronal function, including cell signaling and gene transcription. On the other hand, TNF-alpha is implicated in neurodegenerative diseases such as multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease.

Gelbard says the role of TNF-alpha may depend on how much of the substance is present. In multiple sclerosis, for example, an overabundance of TNF-alpha can lead to the destruction of myelin, the protective sheath around nerves that enhances the transmission of signals between the body and the brain.

Gelbard is currently investigating promising new strategies for treating individuals with neurologic disorders associated with HIV infection. He and his colleagues believe that high levels of TNF-alpha and another pro­inflammatory cytokine, platelet activating factor, may be an indication of inflammation in the brain, as well as a sign of potential neuronal damage from HIV infection.

“There are signs that TNF-alpha is readily reproduced in HIV,” he says. “Inflammation comes first, followed by neuronal damage. TNF-alpha plays a profoundly unpopular role in this cascade of events.”

Researchers are now studying how to regulate TNF-alpha production to treat disease, but Gelbard says the work is complicated: No medications have been developed yet to block its production effectively, and many molecules under investigation are too large to cross the blood-brain barrier and target TNF directly.

Proinflammatory Cytokines and Pain

Watkins and her colleagues at Colorado have shown that proinflammatory cytokines also play a role in increased pain sensitivity caused by sickness. Such an increase is one of many sickness responses created by the central nervous system but triggered by immune activation; others include fever, increased sleep, and decreased appetite.

In research published early this decade, Watkins found that glia, nonneuronal cells that participate in central nervous system signal transmission, become activated under certain conditions, such as when immune cells signal the central nervous system to trigger sickness responses. She discovered that pathological pain can be created by viruses, nerve damage, and other pathological processes that tap into the glial pathway, triggering spinal cord glia to become activated and to release substances that amplify pain. Key among these, she says, are pro­inflammatory cytokines.

Researchers, recognizing the importance of proinflammatory cytokines in the induction of pain, have launched multiple trials to test cytokine-suppressing drugs in animal models. These drugs either disrupt the action of proinflammatory cytokines or interrupt their signaling.

“Understanding that glial activation and the release of proinflammatory cytokines are a powerful driving force for exaggerated pain opens up new ways to approach effective clinical pain control,” Watkins says.