Cytokines - A Missing Link in Internal Diseases?

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Biology 202

2006 First Web Paper

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Cytokines - A Missing Link in Internal Diseases?

Jessica Engelman

Initially, this project was supposed to focus on allergies and depression and the studies finding a positive correlation between the two, but as my research progressed, I discovered similar correlations between depression and chronic fatigue, then depression and central hypothyroidism, then allergies and inflammation, then inflammation and cancer, and then of many other diseases all caused by internal factors, and all of these linked by a single shared trait—an overabundance of certain cytokines. Cytokines are a type of protein that is secreted by a variety of cells (primarily helper-T cells and macrophages) that serve a variety of purposes, such as inducing or inhibiting inflammation, regulating blood cell formation, and prompting the immune system. Not all cytokines cause the same reaction—different kinds of cytokines can even counter each other, so although confusing, use of cytokines' specific names is imperative. (1)

To best understand how all the above-mentioned diseases are connected, let us go through them one-by-one, starting with inflammation, and focusing on the role cytokines play. Scientists are continually discovering the impact inflammation has on the body; it plays a role in arthritis, PMS, heart disease, gingivitis, stroke, Alzheimer's disease, and cancer for starters. Not that inflammation is all bad, it's a necessary part of the immune system that helps heal injuries and prevent infection. A major factor in inflammation is cyclooxygenase-2 (Cox-2)—an enzyme that produces cytokines. Cox-2 converts arachidonic acid (an omega-6 fatty acid) into inflammation-inducing tumor necrosis factor alpha (TNF alpha) and cytokines interleukin-1 (IL-1) and interleukin-6 (IL-6). IL-1 and TNF alpha then prompt the release of free radicals, which can destroy foreign objects, but also wreck havoc on the body, destroying cells and their DNA. (2)

Meanwhile, a study conducted by Marshall, O'Hara, and Steinberg on allergies and fatigue and mood indicated patients with ragweed allergies reported during ragweed season higher general fatigue, mental fatigue, and feelings of depression, and reduced motivation, alertness, attentiveness, and pleasure than during winter (this is contrary to the general population which tends to feel more depressed during winter). However, they did not indicate higher levels of physical fatigue, which the researchers took to indicate an affect on the central nervous system by the allergic reaction. If this is true, it also explains why allergies can negatively impact scores on tests of mental activities. Rather than relying on the traditional explanation that the physical symptoms of allergies lead to feeling depressed because feeling unwell physically makes one feel unwell emotionally, they propose a different explanation. Ragweed can prompt the release of IL-1 and TNF alpha in the lungs, causing inflammation and allergic and asthmatic reactions. Additionally, this inflammation may increase sensitivity of the central nervous system (specifically the vagus nerves); this increased sensitivity may in turn incite symptoms of depression. Marshall et. all cite several studies connecting depression with increased levels of TNF alpha, IL-1, and IL-6 in cerebrospinal fluid of test subjects injected with an endotoxin, similar to levels in severely depressed patients. Rats bred to have an extra-sensitive CNS (like that of allergy sufferers) exhibit symptoms of depression as well. Additionally, IL-1 increases sensitivity to psychological stresses, which leads to a higher susceptibility to depression. (3) Although this may seem slightly far-fetched, the statistics from several other studies on allergies, asthma, and depression support this theory. For instance, in a study conducted in Hungary by Kovács, Stauder, and Szedmák, 32.2% of subjects with allergies scored above the normal level of depression, 12.5% had clinically significant depressive symptomatology (the national averages were 22.4% and 8.3%, respectively), and those with perennial allergies and asthma scored higher on the depression scale than those with other types of allergies. Additionally, the worse the allergic symptoms, the higher the level of depression indicated. (4) A study by Rimington, Davies, Lowe, and Pearson shows a positive correlation between asthma and depression and anxiety, although they suggest that the asthma might be caused by the depression, rather than the other way around. They found that symptom scores beyond the effects of lung function could be explained by scores on the Hospital Anxiety and Depression scale that was administered to subjects. (5) Mancuso, Margaret, Peterson, and Charison conducted a study that also showed a positive correlation between depression and health-status of asthma, although they did not indicate whether the correlation was causational. (6) So whether causational or not, there is a clear correlation among allergies, asthma, inflammation, and depression, with the possible link of cytokines.

Now it starts getting interesting. IL-1, IL-6, and TNF also play a role in hypothyroidism, AKA low thyroid. In hypothyroidism, there are insufficient levels of thyroid hormones, leading to the upset of metabolism and homeostasis. (7) The thyroid gland secretes the hormones T4 and T3, which maintain metabolism in cells. T4 can be converted to the more active T3 with the help of cortisone, but our aforementioned cytokines can prevent this conversion. Thus, high levels of cytokines result in lower levels of T3, leading to hypothyroidism. (8) Things get stranger upon realization that Candida (a digestive disease caused by bacteria or yeast) can lead to an increase in IL-1, IL-6, and TNF. (7) So to wrap up, increased levels of inflammatory cytokines caused by Candida, allergies, or asthma can lead to depression, inflammation, and hypothyroidism. Inflammation can lead to arthritis, PMS, heart disease, and cancer while hypothyroidism can lead to a range of problems, including fatigue, susceptibility to cold and flu viruses, high sensitivity to cold, and disruption of the reproductive system.

At first this research was fairly uninspiring; the connection between allergies and depression was interesting but nothing revolutionary. However, I started noticing a strange trend. The more I discovered about cytokines, the more health problems I came across that my mother has had at one point or another. I ended up calling her after seeing the connections between allergies, depression, and chronic fatigue (all problems she has had at some point or another) and asked her to list out the other major diseases she's had to see if I could get lucky and find a connection among these and cytokines as well. She listed Candida, hypothyroidism, and PMS—a few google searches later, I found sources connecting these to the abnormal levels of cytokines. Imagine the excitement of accidentally finding a link between every major medical problem in an individual—even more so when you find the link on your own! Of course this all sounded too easy, but further research into the subject showed these were even the same types of cytokines involved in these medical conditions: IL-1 and IL-6, along with TNF. Although I can't do any more research in time for this paper, I want to continue reading up on cytokines to see if I can find any other connections. The strangest part is, I found very few sources that had also connected the dots—-one of which is a website listing the many diseases that can be brought about by Candida (although it does not cite cytokines as being the primary cause for most of the conditions, since fungus, bacteria, and yeast growth is a more prominent result of Candida). (7) Additionally, the sources that found correlations between the other diseases (such as allergies and depression) were fairly recent and indicated that many correlations made ten or more years ago were merely speculative or based on case studies, and the cytokine link is an idea from only the last decade or so.

This indicates a problem with the approach of many scientists and doctors when it comes to understanding and healing the body. Many conventional doctors ignore medical problems other than the one at hand. When my mother was first trying to cure the above-mentioned medical problems ten years ago, she said only the doctors specializing in alternative medication would try to find the underlying causes of a disease and cure that one, instead of just prescribing medication to relieve the visible symptoms. All four cited studies on allergies/asthma and depression concluded that further research in the area is recommended to better understand how the three are related, and that doctors should start taking into consideration depression and other psychological factors that could influence (or be influenced by) the allergic reactions. After all, if it is depression leading to an asthma attack, asthma medication may not be sufficient, and if depression is caused by allergic reactions, patients would be much better-off if they could eliminate their allergies than if they merely took anti-depressants. Perhaps medical science needs to be more open to the possibility of other contributing factors and give more credit and attention to the many alternative methods that do consider connections within the body. As an article on inflammation remedies suggests, instead of turning to conventional drugs that target only the immediate problem, we should be looking into remedies that correct whatever condition is causing the immediate problem. This article recommends a dietary change to relieve excessive inflammation--reducing intake of the omega-6 fatty acids that can be converted into IL-1, IL-6 and TNF and increasing intake of the omega-3 fatty acids that can be converted into anti-inflammatory compounds. More specifically, this means eating more cold-water fish, leafy green vegetables, extra-virgin olive oil, and flaxseed, and less vegetable oil and processed foods. Additionally, eating more foods high in antioxidants (such as pomegranates and blueberries) will help to neutralize the damage caused by free radicals. Anti-inflammatory drugs such as Celebrex and Vioxx only target the Cox-2 and never address any underlying dietary problems. (2)

All the while, we must remember to consider the effect any disease has on the brain. New discoveries are being made every year connecting functions in the nervous system and the rest of the body. An article from the Psychiatric Times recognizes the importance of omega-3 fatty acids in curbing inflammatory cytokines, and cites evidence that a lack of omega-3 may lead to not only symptoms of depression, but also schizophrenia, alcoholism, and bipolar disorder. Yet even this article states that much of this is "suggestive" and needs further research before becoming accepted fact. (9) We are still not certain how cytokines affect the brain, but this question clearly deserves our attention. Even more importantly, though, we should not lose sight of the other end as well--but rather to always consider the cause in addition to the result.



2)Natural Remedies for Inflammation

3)Allergies, Fatigue Level, and Mood

4)Severity of Allergic Complains, The Importance of Depressed Mood DOI code - doi:10.1016/S0022-3999(02)00477-4

5) Relationship between anxiety, depression, and morbidity in adult asthma patients

6) Effects of Depressive Symptoms on Health-Related Quality of Life in Asthma Patients



9) Dietary Fatty Acids Essential for Mental Health

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