Why Cytokines Make You Feel Like Sh*t

Cytokines are a group of proteins involved in cell-to-cell communication. Cytokines are produced by various immune cells including mast cells, B cells, and T cells, but can also arise from tissue cells like fibroblasts and endothelial cells. Examples of cytokines include the chemokines, interferons (IFN), interleukins (IL), lymphokines, and tumor necrosis factors (TNF).

Unlike hormones, cytokines are found in smaller concentrations and work less specifically. They play important roles in health as well as disease. Cytokines are at the center of regulating the body’s response to infection, immune challenges, inflammation, trauma, and cancer.

Cytokines can have anti-inflammatory or inflammatory activity. Many cytokines are produced during oxidative stress (free radical production) and can trigger the release of even more cytokines that produce oxidative stress. This creates a feed-forward pro-inflammatory state that is effective for stimulating fever to fight infection but can also contribute to chronic inflammation seen in chronic conditions.

Why Cytokines Make You Feel Like Sh*t

When one falls sick, similar experiences occur near universally. The ill person has little motivation to eat, experiences fatigue and malaise, has significant changes in sleep patterns, and no desire for social interaction. Some sick individuals also have exaggerated responses to pain and cognitive problems including failure to concentrate.

Virtually all mammals experience these sickness behaviors. They are part of a long held homeostatic reaction the body uses to fight infection. These symptoms allow us to rest and recover, and moreover prevent future injury or insult. It wasn’t until the 1990’s that it was determined that cytokines are responsible for much, if not all, of these sickness behaviors.

How did we find this out? In the early days, recombinant cytokines were administered to animals and cancer patients to observe responses. Injections of cytokines led to neurotoxic side effects and subjective malaise, fatigue, weakness and lethargy. The main culprits were cytokines including IL-1, TNF-alpha, and IFN-alpha.

Administration of cytokines to non-psychiatric patients produces depressive episodes in the majority. In cancer patients receiving therapeutic cytokine therapy, 30-50% develop depressive episodes, anxiety, sleep disturbance, and cognitive problems. Those with chronic hepatitis also receive therapeutic cytokine therapy and readily develop depressive, cytokine-sickness behaviors. Some of these patients administered cytokine therapy even develop flu-like syndrome including low grade fever and tender lymph nodes.

Cytokines in the Brain

Cytokines are large proteins, which generally cannot cross cell membranes nor the blood-brain barrier. However, regions around the brain’s major sensor, the hypothalamus, allow for the passage of some peripheral cytokines. There are also transporters that allow some cytokines to pass. Another mechanism for which cytokines can act on the brain is indirectly via the vagus nerve. The vagus nerve extends from the brain stem throughout the anterior cavities of the body. Because the nerve is widespread, it can sample information from various sites where peripheral cytokines circulate and transmit this information back to the brain. Once the message is received by the brain, microglia and macrophages produce complementary cytokines.

How Cytokines Effect Neurotransmitters

It was Michael Maes, a sensible psychiatrist and prolific ME/CFS researcher, who first posed the idea that inflammatory cytokines and the resulting cytokine-induced sickness behaviors were central to depression, and later to ME/CFS. In his model, inflammatory cytokines activate the enzyme indoleamine 2,3 dioxygenase (IDO). This key enzyme breaks down tryptophan, an essential amino acid necessary for the synthesis of serotonin. Serotonin is of course the neurotransmitter most associated with depression, cognition, mood, and anxiety. Breakdown of tryptophan generates neurotoxic metabolites like quinolinic acid and kynurenine. So when IDO is upregulated by inflammatory cytokines, there is an excess of these neurotoxic byproducts with brain deficiencies of tryptophan and serotonin.

The tryptophan-kynurenine pathway connects metabolism and immunity. It plays an important role in inflammation while also playing an opposing role in the control of acute and chronic infections. Abnormalities in this pathway have been proposed as a central mechanism in ME/CFS by Maes, but also by Blankfield and Ron Davis’ metabolic trap theory. Metabolites associated with this pathway can be evaluated through urinary organic acid testing.

Cytokine-Induced Sickness Behavior in ME/CFS

Cytokine-induced sickness behaviors are the cardinal symptoms of ME/CFS, and perhaps also in fibromyalgia. Studies suggest the more inflammatory cytokine load, the more severe the symptoms. An acute exacerbation of ME/CFS—a flare or a crash—can also be explained by cytokines. Strenuous activity, viral infection, food sensitivity, xenobiotic exposure, and autoimmune processes all have the potential to stimulate overproduction of pro-inflammatory cytokines resulting in accentuated sickness behaviors. The cytokine IL-1 when administrated has been associated with cognitive and memory problems as is upregulated in ME/CFS. You can read more about cytokines and inflammation in ME/CFS and fibromyalgia in a prior post. ME/CFS and fibromyalgia are Inflammatory Conditions

Strategies to Combat Cytokine-Induced Sickness Behavior

Since cytokines are responsible for the myriad symptoms associated with ME/CFS, treatment targeted to antagonize cytokine receptors may prove to be a key treatment approach in the future. Both pharmaceuticals and nutraceuticals are available to serve these purposes. Alternately, administrated of anti-inflammatory cytokines, such as IL-11, may also be an option to balance cytokine signaling. Trials of these drugs have thus far given mixed results, mostly negative. However, the common antidepressant Paroxetine (aka Paxil and Seroxat) has been used favorably to reduce cytokine-induced sickness in cancer patients receiving cytokine therapies.

Some patients report symptom improvement through the use of nutraceuticals that reduce inflammatory cytokines. Dr. Craig’s favorite is CytoQuel from Researched Nutritionals. It includes bioavailable curcumin as well as resveratrol, N-acetyl-cysteine (NAC), and others targeted to central pathways of inflammation. You can read more about supplements that reduce inflammation in a prior post. 5 Supplements to Reduce Neuroinflammation

Alternately, devices will soon be available that stimulate the vagus nerve to alter the messages being sent to the brain thereby reducing the inflammatory message. At present, vagal nerve stimulators are approved for treatment-resistant depression and epilepsy. A severing of the vagus nerve has been shown to eliminate many of the sickness responses when subjects are injected with cytokines. This therapy is no longer in use due to the high risk of adverse effects.

References

Kelley, K. W., Bluthé, R.-M., Dantzer, R., Zhou, J.-H., Shen, W.-H., Johnson, R. W., & Broussard, S. R. (2003). Cytokine-induced sickness behavior. Brain, Behavior, and Immunity. 17(1), 112–118.

Myers, J. S. (2008). Proinflammatory Cytokines and Sickness Behavior: Implications for Depression and Cancer-Related Symptoms. Oncology Nursing Forum, 35(5), 802–807. doi:10.1188/08.onf.802-807 .

Poon, D. C.-H., Ho, Y.-S., Chiu, K., & Chang, R. C.-C. (2013). Cytokines: How important are they in mediating sickness? Neuroscience & Biobehavioral Reviews, 37(1), 1–10.

Dantzer, R., & Kelley, K. W. (2007). Twenty years of research on cytokine-induced sickness behavior. Brain, Behavior, and Immunity, 21(2), 153–160.