A Few Cytokines and Their Actions
The purpose of this chapter is to give the reader a glimpse of the vast and diverse powers of cytokines in sickness and disease. It is not intended for the reader to remember or understand every facet and detail of cytokine action. The main point is to appreciate the multifaceted activities of cytokines. The scientific literature on cytokines is enormous (over 100,000 published scientific papers) and growing explosively, so this chapter makes no attempt to cover the topic thoroughly.
There are at least 28 immune cytokines and each one has a broad spectrum of actions.1,2 To wade through information on all of them would lead to tedium and hopeless confusion Instead, IL-1 will be used as the main example, along with comments on IL-6, IL-2, TNF and a few examples of suppressive cytokines. Some explanations for the nasty effects of cytokines will be presented at the end.
Endogenous Pyrogen During the 1930's and 1940's experiments were published suggesting that immune cells, when stimulated, secrete water soluble, biologically active 'factors'. In 1942 Menkin produced fever by injecting animals with liquid from solutions previously containing leukocytes. The mysterious fever provoking substance made by the leukocytes was called endogenous pyrogen (pyrogen=heat producer). For many years scientists could not isolate, purify or identify endogenous pyrogen because it was produced in such minute amounts.
At the 1979 International Lymphokine Workshop in Switzerland, endogenous pyrogen was officially named interleukin-1. In addition to endogenous pyrogen, there were many other reported 'factors' which were found to be the same as interleukin-1. For example, lymphocyte activating factor, mononuclear cell factor, leukocyte endogenous mediator, epidermal derived thymocyte activating factor, proteolysis inducing factor, synovial factor, catabolin, fibroblast proliferating factor, osteoclast activating factor, hepatocyte activating factor and serum amyloid A stimulating factor were shown to be the same as interleukin-1. One conclusion is clear: interleukin-1 has many different activities.
Cellular Sources of IL-1 When activated, monocytes in the blood along with macrophages residing in tissues throughout the body, including the brain, are the main producers of IL-1. But there are many other cell types capable of secreting IL-1. Several types of lymphocyte make IL-1: helper T-lymphocytes, B-lymphocytes and natural killer lymphocytes. Endothelial and smooth muscle cells in blood vessels make IL-1 as do three different kinds of brain cells: astrocytes, microglia and glioma cells. Keratinocytes, the principal skin cells and Langerhans cells (a macrophage like cell) found in the skin can secrete IL-1. A number of other cell types can manufacture IL-1: kidney cells; fibroblasts (these cells make fibrous connective tissue); chondrocytes (these cells make cartilage); epithelial cells of the cornea and thymus; norepinephrine producing nerve cells; neutrophils (inflammatory immune cells) and dendritic cells (specialized cells found in the lymph glands).
Clearly, there are a remarkable number of cell types that are able to produce IL-1, but monocytes and macrophages are the major, consistent producers. Immune system activation is usually needed to stimulate the other cell types to secrete IL-1. Therefore, IL-1 is primarily under immune system control.
Induction of IL-1 Production Many different pathogens and substances can stimulate monocytes and macrophages to make and secrete IL-1. A wide range of viruses, bacteria, spirochetes, fungi and other infectious agents (see refs 34-36 in IL-1) induce IL-1 production. Antigens (foreign proteins), urate, silica, asbestos and numerous cytokines (IL-1, IL-2, TNF, IFNα, IFNβ, IFNγ, macrophage-colony stimulating factor, transforming growth factorβ) and many other bodymade chemicals induce IL-1 production. Surgery, trauma, tissue damage, organ dysfunction, malignant cells and dying tissue trigger IL-1 release. Recent work on animals and humans has revealed that chronic, severe psychological stress can increase IL-1 secretion.(need refs)
Even though a huge number of pathogens, chemicals and agents can provoke IL-1 production, under normal healthy conditions, little if any IL-1 is secreted. The same is true for the other 27 cytokines. Cytokines aren't secreted unless the immune system and other cells are provoked by some biological or psychological danger.
Actions of IL-1 An incredible number of cell types are profoundly affected by IL-1. T-lymphocytes and B-lymphocytes, which are essential warriors in any war against lethal invaders, can not go to battle without IL-1. Other immune cells, such as natural killer cells, monocytes, macrophages, neutrophils, eosinophils and dendritic cells, are energized by this remarkable cytokine. IL-1 also powerfully regulates nerve cells, astrocytes, microglia, liver cells, fibroblasts, malignant cells and cells essential for cartilage, bone, muscle, blood vessels, pancreas, skin, kidney, pituitary, spleen, adrenals, thymus, intestine, sex glands and cells lining every cavity and vessel in the body. In short, IL-1 can profoundly change the activities of every cell, tissue and organ in the body.
There is more. IL-1 stimulates immune cells and other cells to secrete additional powerful cytokines like IL-2, IL-6, TNF and IFN's. These cytokines go on to stimulate other cells to produce additional cytokines. Thus, IL-1 initiates an astonishing cascade of cytokine secretions. Eventually, at some point during immune activation, the majority of the 28 different cytokines will be secreted.
In response to IL-1, numerous cells begin secreting a variety of other powerful chemicals in addition to cytokines. Consider this: macrophages, which are activated by IL-1, can secrete over 100 different biologically active compounds! They include enzymes, prostaglandins, leukotrienes, thromboxanes and reactive oxygen species. Many of these are important mediators of pain, inflammation and body metabolism. Clearly, the secretion of IL-1 initiates a bewildering number of chemical-biological changes in the body.
IL-1 given to animals or humans triggers a deluge of whole body responses. IL-1 causes: sleep, fever, inflammation, pain, malaise, aching joints, fatigue; irritability, depressed mood, social withdrawal, lack of interest in things, nausea, anorexia, weight loss, fall in blood pressure, muscle wasting, cartilage wasting, bone wasting, increased acute phase proteins, lower blood levels of albumin, zinc and iron, higher blood levels of copper and calcium, increased stress hormone secretion and increased sodium excretion, blood flow to organs, white blood count and inflammatory cells in the joints. Several of these whole body responses will be covered further on page.
IL-1 has powerful effects on the brain. Receptors for IL-1 are found in many areas of the brain including four vital brain structures - hypothalamus, hippocampus, raphe nucleus and locus coeruleus. They control in a fundamental way most of the body's hormones and many of the brain's neurotransmitters, including norepinephrine, dopamine and serotonin. Instinctive behavior, emotions, reactions to physical and psychological stress, and basic drives such as hunger, thirst, sex, pleasure and pain are mediated by these structures. And guess what, these critically important brain centers can be profoundly regulated by IL-1!
IL-1 is directly involved in the signs, symptoms and pathology of an extensive number of diseases such as hypotensive shock, sepsis syndrome (shock), transplant rejection, graft vs. host disease, multiple sclerosis, Alzheimer's disease, Parkinson's Disease, stroke, cancer (T-cell lymphoma, nasopharyngeal carcinoma and Hodgkin's disease), lupus, rheumatoid arthritis, psoriasis, asthma, osteoporosis, alcoholic hepatitis, scleroderma, diabetes, various kidney diseases, dialysis complications, anorexia nervosa, sleep disorders, Crohn's disease (severe inflammation of the intestinal tract), ulcerative colitis, periodontitis (gum disease), sunburn, burns, endometriosis, atherosclerosis, cardiovascular disease and all infectious diseases including AIDS, Lyme disease, tuberculosis and meningitis. Of course many other cytokines are involved in these and other diseases.
The extremely broad and powerful biological effects of IL-1 are unmatched by any classical hormone, yet there are other cytokines, such as TNF, IL-2 and IL-6 which have similar broad biological effects. This brief review of IL-1's actions illustrates the immune system's awesome power and unparalleled ability to control the functioning of the body, including the brain. The secretion of IL-1 and other pleiotrophic cytokines like TNF, IL-2 and IL-6 is, in effect, a declaration of "martial law" by the immune system. During the state of emergency, the immune system wrests control of the body from the brain. The brain becomes a willing pawn, in the service of the immune system's mobilized army.
The name tumor necrosis factor (TNF) was due to early (1962) discoveries of a water soluble 'factor' secreted by activated immune cells that caused tumors to bleed and die (necrosis=death). Unfortunately, the name implies its main action is to kill tumors yet it is much more than a tumor necrosis factor. TNF is a powerful, broad spectrum (pleiotrophic) cytokine with actions similar but not identical to IL-1. It is primarily made by activated monocytes and macrophages, although like IL-1, many other cells can make TNF.
During the 1970's a group of investigators discovered a water soluble 'factor' made by activated immune cells that caused animals to waste (i.e. lose weight and muscle mass). The wasting syndrome found in serious illnesses is called cachexia, hence this factor was called cachectin. In 1985, cachectin was shown to be the same molecule as TNF, so some papers call this cytokine TNF/cachectin.
There are two forms of TNF. The one made by monocytes and macrophages is a small protein composed of 157 amino acids called TNFα. The other form, originally called lymphotoxin, is made by lymphocytes and is now called TNFβ. Even though they are different molecules, they are both considered TNF because they bind with the same cell receptor. Less is known about TNFβ than TNFα, so in this book TNF refers to TNFα.
The extensive number of sources, inducers, actions and disease involvements of IL-1 listed in the previous section are very similar to the sources, inducers, actions and disease involvements of TNF. There is no reason to list them again. The duplication of action by these cytokines is called redundancy. Not only are IL-1 and TNF redundant, but both these cytokines induce each other. IL-1 stimulates cells to make TNF and TNF stimulates cells to make IL-1. Working together, IL-1 and TNF have more powerful effects than each one working alone.
No one knows the reason for redundancy, but most immunologists think it underscores the critical importance of these cytokines for animal and human survival. The immune system, it seems, does not want to stake its life on one molecule like IL-1, just in case for some unforeseen reason IL-1 malfunctions.
This powerful pleiotrophic cytokine has many properties and actions in common with IL-1 and TNF, though there are some important differences. First, both TNF and IL-1 stimulate the production of IL-6, but IL-6 cannot induce the secretion of either IL-1 or TNF. Indeed, there is evidence that IL-6 inhibits the secretion of TNF and IL-1. Second, many of the actions of IL-1 and TNF are vigorously amplified by IL-6. For example, the reported ability of TNF and IL-1 to stimulate the liver to make acute phase proteins may, for the most part, be due to the presence of IL-6. Third, estrogen inhibits IL-6 secretion which contrasts with estrogen's ability to stimulate IL-1 secretion. This probably is an important reason estrogen protects against osteoporosis, since estrogen suppresses IL-6 and IL-6 causes bone loss. Fourth, the production of IL-6 increases with age, whereas most cytokines decrease with age. This has powerful implications for degenerative brain diseases like Parkinson's Disease and Alzheimer's disease, because IL-6 is linked with these pathologies and like IL-6, they increase with age. (Note: many other cytokines are also linked with brain degenerative diseases).
IL-2 is made by lymphocytes rather than monocytes or macrophages. Many of IL-2's most important actions are intended to activate lymphocytes. Some of IL-2's vital actions are not easily duplicated by other cytokines. For example, in order to produce an army of lethal lymphocytes to kill malignant cells or invading microorganisms, specialized lymphocytes need to reproduce rapidly. IL-2 stimulates lymphocyte reproduction better than any other cytokine. In fact, no other cytokine can adequately replace IL-2. The lack of redundancy is quite surprising
In addition to its effects on lymphocytes, IL-2 is also a broad spectrum cytokine with some actions similar to IL-1 and TNF. One area of intense interest is the experimental use of IL-2 and IL-2 activated lymphocytes for the treatment of cancer, but many nasty, unwanted effects occur. Capillary leakage of blood is one of the most dangerous. Other unwanted effects include fall in blood pressure, heart and lung problems, kidney dysfunction, nausea, diarrhea, liver abnormalities, anemia and serious psychiatric symptoms, including hallucinations, paranoid delusions, anorexia, fatigue, malaise, loss of interest, decreased energy and sleep disturbances. Many of these pernicious effects may also be due to the other cytokines IL-2 induces.
Another area of intense interest is the role of IL-2 in the brain. IL-2 has potent effects on nerve cell growth and survival, nerve impulses and neurotransmitter activities. IL-2 can be made by nerve and glia cells in the brain and IL-2 molecules and IL-2 receptors are found throughout the brain. In addition, it can pass through the blood-brain barrier, meaning that IL-2 secreted by activated lymphocytes in lymph glands, spleen, gut or anyplace outside the brain can travel to the brain and affect brain function. IL-2 appears to be involved in brain development and the regulation of sleep, arousal, memory function, movement, sickness behavior and psychiatric disease including depression and schizophrenia.
After the immune system is activated, how does it eventially turn itself off? Part of the answer is by secreting immunosuppressive cytokines. Interleukin-10, made exclusively by T-lymphocytes, is the most potent immunosuppressive cytokine known. IL-10 suppresses macrophage and T-lymphocyte function along with vigorous suppression of many cytokines like IL-1, IL-6, and TNF. On the other hand, IL-10 paradoxically stimulates the production of antibodies! -an example of the devilish complexity of cytokine actions. Another cytokine with a mixture of suppressive and stimulating actions is IL-4. It suppresses macrophages and their production of IL-1 and TNF, yet it stimulates lymphocytes and antibody production.
A third suppressive cytokine exhibiting complex, conflicting actions is transforming growth factor-beta (TGFβ). It's made by macrophages, lymphocytes and many non-immune cells. When administered intravenously TGFβ has a broad spectrum of suppressive actions including suppression of antibody production, inflammation, secretion of IL-1, IL-2, IL-6 and TNF, and macrophage and lymphocyte function. In contrast, when given locally (i.e. injected under the skin or in joints), TGFβ increases cytokine secretion and inflammation. Nevertheless, animals unable to make TGFβ develop a debilitating systemic inflammatory condition. On balance TGFβ is a powerful immunosuppressive cytokine. It is normally secreted by activated immune cells, but not during the initial stages of activation. TGFβ is usually secreted after the 5th or 6th day of immune activation.
Another suppressive cytokine is interleukin-1 receptor antagonist (IL-1RA). It's like an inactive form of IL-1 that interfers with IL-1. It binds with IL-1 receptors, thereby blocking the actions of IL-1 hence the name interleukin-1 receptor antagonist. IL-1RA is always secreted, in copious amounts whenever IL-1 is secreted, which indicates that the immune system is always trying to modulate the robust power of IL-1. Recent research shows that impaired IL-1RA secretion may be one cause of some chronic inflammatory diseases.
Another means of controlling the unparalleled power of cytokines is by secreting soluble cytokine receptors, such as soluble TNF receptors (sTNFr) and soluble IL-2 receptors (sIL-2r). Whenever activated immune cells are secreting TNF and IL-2, they are also releasing sTNFr and sIL-2r. These soluble receptors bind with TNF and IL-2 in blood and tissue fluids, thereby impeding these cytokines from doing their work on various target tissues.
An additional way immune cells control themselves during immune activation is by telling the adrenal glands to release the immunosuppressive hormone cortisol. Here is how it is done: IL-1, IL-2, IL-6 and TNF stimulates the hypothalamus to release corticotrophin releasing factor (CRF). CRF orders the pituitary to secrete ACTH into the blood stream. ACTH stimulates the adrenals to release cortisol. Cortisol, in turn, reduces IL-1, IL-2, IL-6 and TNF production. It also stimulates the secretion of TGFβ, an immunosuppressive cytokine.
Cytokines And Their Nasty Effects. As we have seen, many of the effects of cytokines on the body are either unpleasant (fever, chills, inflammation, pain, headache, malaise, aching joints, weakness, sleepiness, fatigue, inability to concentrate, irritability, depressed mood, social withdrawal, lack of interest in things, nausea and anorexia) or debilitating (weight loss, muscle wasting, cartilage wasting, bone wasting and lower blood levels of albumin, zinc and iron). Why do cytokines have such unpleasant and seemingly debilitating effects? The general answer is quite simple: the immune system will do anything to save the body from internal or external dangers, even if it hurts. The following examples explain the benefits of these nasty effects.
Fever36 What is good about fever? First, the body can produce immune cells and antibodies much more rapidly at higher temperatures. Second, certain bacteria and viruses and some tumors reproduce slower at high temperatures. The more rapid division of immune cells combined with the slower reproduction rate for some bacteria and viruses during fever is a very effective strategy to overwhelm and defeat any invading microorganism. Indeed, to a great extent the battle between invaders and the immune system is merely a race to see which side can produce soldiers for the battle more rapidly. If the immune system can produce lethal soldiers quicker than an invading bacteria can reproduce, then the immune system will prevail. If not, the invading microorganism will probably win and the patient will die. Thus fever is a vital process to help the body survive in a world filled with dangerous pathogens.
Prior to this century, fever was assumed to be harmful and dangerous. Indeed, for almost a thousand years, fever was understood to be a disease. Based on this concept of disease, fever reduction was an urgent and rational goal of medical treatment. This century fever was finally recognized as a reliable sign of disease, rather than the disease itself. Biomedical science now knows that cytokines raise body temperature in order to speed up immune system activity. Nevertheless, fever is usually viewed by the public as a harmful phenomena, one that should be eliminated by taking aspirin, Tylenol or other antipyretics. This erroneous view is commonly reinforced by physicians, nurses and a plethora of advertisements. One wonders when the primitive attitudes of practicing physicians towards fever will finally catch up with current biomedical knowledge on cytokines and fever.
There are situations where cytokines push body temperature too high and intervention with aspirin or Tylenol is necessary. For example, temperatures above 104° F in young children often provokes convulsions. Temperatures above 106° F in children or adults can cause irreversible brain damage.
Inflammation37 It seems everybody considers inflammation to be a harmful and unnecessary phenomena. The usual medical strategy for inflammation is to reduce it with various anti-inflammatory drugs or ice. Our attitudes towards both fever and inflammation are very similar, namely, eliminate them, as if they were diseases. Of course, they are not diseases. Fever and inflammation are defenses mediated by cytokines and they are reliable signs of immune system activation.
Inflammation is one of the most important defensive maneuvers the immune system employs. The process of inflammation walls off and isolates infections and tissue damage, thereby preventing the spread of infection and pathology to the rest of the body. Without inflammation we would all be dead, because the simplest infection would quickly enter the blood and from there, to all body tissues. Inflammation also permits more blood, oxygen, nutrients and immune cells to enter the infection site. For the most part, inflammation is very beneficial.
As with fever, inflammation in some situations can be too much of a good thing. The most clear cut example of harm due to inflammation can be found in the brain. Brain swelling, due to trauma, infection, tumor or stroke, is very dangerous because there is no room to swell inside the skull. Pressure in the brain goes up sharply, causing nerve and other cells in the brain to die. Dead brain cells trigger more immune activation and inflammation. A viscious cycle of more cell death and increased inflammation can occur. Prevention of brain inflammation is an urgent treatment goal in these cases.
Lower Serum Iron38,39,40 Serum iron is usually depressed during serious infection. For many years physicians and dietitians thought it was a sign of iron deficiency. We now know that depressed serum iron occuring with infection is an immune system maneuver mediated by IL-1 and other cytokines. This is how it happens. IL-1 stimulates the liver to release transferrin and lactoferrin. These compounds bind with iron in the blood, transfer it to the liver, thereby reducing the amount of iron in the blood.
With serious infection serum iron is often low enough to be classified as iron deficiency anemia, but it is not true iron deficiency anemia because IL-1 merely redistributes the iron. IL-1, via transferrin and lactoferrin, removes iron from the blood and stores it in the liver. Liver and bone stores of iron are usually adequate during immune activation.
Why does the immune system lower serum iron during infection? Answer: Iron is a critical growth factor for most bacteria, hence lower iron availability slows down bacterial growth. Reduced serum iron, because it deprives bacteria of an essential nutrient necessary for growth and replication, is another immune system strategy for defending the body.
Acute Phase Proteins and Low Plasma Albumin41,42,43 Albumin is the principal protein in blood plasma, accounting for about 60% of the total. It helps maintain normal osmotic pressure and acts as a transporter of large molecules in the blood. Plasma albumin level is often used as an indicator of protein nutritional status, since a diet very low in protein does cause albumin and total plasma protein to fall.
Several cytokines, including IL-1, IL-6 and TNF also sharply reduce plasma albumin levels. These cytokines tell the liver to stop making albumin. At the same time they instruct the liver to make more acute phase proteins, so called because they rise during the acute phase of an illness. Total plasma protein remains about the same, since elevated acute phase proteins make up for the reduced albumin.
No one has discovered any immune benefits due to lowered albumin. The main reason it is lowered is to permit the liver to make more acute phase proteins. These special proteins are remarkably beneficial for host defense. They assist immune cells in carrying out their life saving functions. For example, immune cells can kill bacteria and viruses more effectively when acute phase proteins are present. In addition, they can neutralize inflammatory agents, help minimize tissue damage and participate in tissue repair.
Muscle Wasting44,45,46 Muscles are the storehouse for glutamine, an amino acid necessary for immune cell metabolism and proliferation. Glutamine is an essential fuel for immune cells, similar to the importance of glucose for nerve cells. Activated immune cells have a very high demand for glutamine.
Muscle wasting releases large quantities of glutamine and other amino acids. Glutamine is used by the activated immune cells for energy metabolism and related functions. The other amino acids released from muscle are utilized by the liver to help make acute phase proteins. Thus, muscle wasting is an integral part of the immune systems defense of the body.
Muscle wasting used to be thought of as a deleterious process. We now can see that it is a necessary and beneficial process. Muscle wasting is caused by IL-1, IL-6, TNF and IFNγ. The stress hormone cortisol works with these cytokines to accelerate the process. Muscle wasting is another example of the immune systems ability to take over the control of the body in order to wage a more effective war against infection, trauma or malignancy.
These insights have revealed that muscles play an important storehouse role essential nutrients needed by an activated immune system. This means that persons with good muscle mass are able to survive more serious infections or injuries than persons with little muscle mass. Indeed, seriously ill patients who are underweight (which usually indicates poor muscle mass) have much higher death rates in hospital.
Elevated Cortisol47,48,49 Cortisol, an important anti-inflammatory and immunosuppressive hormone made by the adrenal cortex, is always elevated during infection, injury and disease. The mechanism by which cortisol is elevated under these conditions had been a mystery for many years. As discussed previously, we now know that cytokines cause the elevated serum cortisol levels. The immune system wants copious amounts of cortisol to be present during infection, injury and disease.
Why would the immune system want large amounts of the body's most immunosuppressive and anti-inflammatory hormone present during infection, injury and disease? First, cortisol stimulates muscle wasting and acute phase protein production. Second, the immune system (and brain) wants to keep the activated immune cells well behaved when they are outside the 'war zone', that is, outside the walled off, inflamed areas where infection or trauma has occurred. If immune cells were as active throughout the body as they are at inflamed sites, then there would be massive amounts of tissue damage, inflammation and pain everywhere in the body every time an infection or injury occurred.
Sleep50,51,52,53 Fatigue and increased sleep are typical signs of infection and other serious illnesses. Interleukin-1 and several other cytokines are responsible for the fatigue and increased sleep that occurs with immune activation. One benefit of fatigue and sleep is a reduced energy requirement by muscles and other tissues, thereby making more energy available for the enormous metabolic demands of an activated immune system.
Probably the most important benefit of sleep has to do with prolactin secretion. Prolactin is a multifunctional pituitary hormone secreted by both males and females from infancy through old age. Sleep greatly increases the amount of prolactin secreted. This is extremely important because prolactin has powerful energizing effects on the immune system. It acts as a cofactor with IL-2. Indeed, IL-2 needs prolactin to carry out many of its functions. For example, lymphocytes, in order to divide and proliferate, require both IL-2 and prolactin. Proliferation of lymphocytes is the fundamental process of producing more immune soldiers in order to overwhelm invading pathogens.
A second immunological property of prolactin is its ability to increase the number of IL-2 receptors on lymphocytes. These receptors make lymphocytes more responsive to the stimulating effects of IL-2. A third beneficial property is its stimulatory effect on the secretion of IFNγ, a powerful cytokine produced by activated lymphocytes.
During infection and trauma, it is of life and death importance for the immune system to be activated quickly, including rapid proliferation of lymphocytes and other immune cells. This permits the immune system to battle and destroy the enemy before the enemy can get the upper hand. We have seen that sleep, because of the increased prolactin secretion during sleep, helps mobilize the immune system. In fact, sleep is an integral part of immune system activation. The bottom line: when you are sick, sleep as much as you can.
Mood Changes With Cytokines Animals and human volunteers given cytokines usually undergo mood and behavioral changes. Animals sleep excessively, lose interest in their surroundings, stop exploratory behavior, appear fatigued and lethargic. Human volunteers, after their first or second injection of cytokine, invariably experience flu like symptoms such as aching muscles and joints, malaise, fever, chills, headache and fatigue. With daily doses of cytokine, the aches and pains, headache, fever and malaise only last about a week.
If cytokines have been given to animals or humans for more than seven consecutive days, then body temperature usually goes back to normal even in the face of continued cytokine administration. Cytokines don't appear able to keep body temperatures raised for extended periods of time. Consequently fever is not a reliable sign of chronic (i.e. long term) immune system activation. This is an extremely important observation, since fever is universally assumed by both professionals and lay people to be the most reliable and consistent sign of immune system activation available. Clearly, it is not. Fever is only a reliable sign during the first week or so of immune system activation.
Cytokines given chronically (i.e. more than 10 days) result in a different set of symptoms. Fever is usually not present. Varying combinations of neuropsychiatric symptoms are usually more prominent, such as, fatigue, loss of interest in things, apathy, inability to concentrate, poor attention span, headache, irritability, anxiety and depression. In most subjects, the symptoms are mild, but in almost all the experiments, between 10 and 50% of the subjects report severe and debilitating symptoms.
The neuropsyciatric symptoms induced by cytokines are further examples of the immune system's ability to declare 'martial law' and to take over command and control of both body and mind. By inducing malaise, fatigue, sleep, headache, apathy, irritability, lack of interest and depression, the immune system is commanding the patient to stay in bed, to rest and to keep away from people. The cytokines act to immobilize the patient physically, intellectually, socially and emotionally. The only thing the patient wants to do is to rest, sleep and avoid people.
The mood and behavioral effects of cytokines have a number of beneficial effects on survival. First, the malaise, fatigue and sleepiness forces the infected person to rest. This permits the body to devote all its energy to fighting the invading microbes or repairing the wounds. Second, the patient sleeps more. During sleep the body is able to produce many more brave new soldiers (lymphocytes) to take up battle with the enemy. Third, the apathy, lack of interest and appetite helps to keep the patient in bed. Fourth, the irritable, antisocial and withdrawn mood helps keep the sick person away from other people, thereby preventing the spread of the disease to other members of the community. Paradoxically, the antisocial behavior benefits society as a whole.
Next chapter: Depression
Chapter 5 References
1. Burke F, Naylor MS, Davies B, Balkwill F. The cytokine wall chart. Immunol Today 14:165-70, 1993.
2. Balter M. Cytokines move from the margins into the spotlight. Science 268:205-6, 1995.
3. Dinarello CA. "Endogenous pyrogen and the early history of cytokine research." in Human Monocytes. M Zembala, GL Asherson, eds. Academic Press, San Diego pp177-190.
4. di Giovine FS, Duff GW. Interleukin-1: the first interleukin. Immunology Today 11:13-20, 1990.
5. di Giovine FS, Mee JB, Duff GW. "Immunoregulatory Cytokines" in Therapeutic Modulation of Cytokines. B Henderson, M Bodmer, eds. CRC Press, 1996 pp 38-60.
6. Phospholipase A2- a mediator between proximal and distal effectors of inflammation. Immunology Today 12:143-146, 1991.
7. Dinarello CA, Wolff, SM. The role of Interleukin-1 in disease. New Engl J Med 328:106-113, 1993.
9. Rothwell NJ, Dantzer RD, eds. Interleukin-1 In The Brain. Pergamon Press, New York, 1992.
10. Cunningham ET, Wada E, Carter DB et al. In situ histochemical localization of type 1 receptor messenger RNA in the central nervous system, pituitary and adrenal gland of the mouse. J Neurosci 12:1101-14, 1992.
11. Cunningham ET, DeSouza EB. Interleukin 1 receptors in the brain and endocrine tissues. Immunol Today 14:171-6, 1993.
12. Grzelak I, Olszewski WL, Rowinski W. Blood mononuclear cell production of IL-1 and IL-2 following moderate surgical trauma. Eur Surgical Res 21:114-22, 1989.
13. Beutler B, Cerami A. Cachectin:more than a tumor necrosis factor. New Engl J Med 316:379-85, 1987.
14. Tracey KJ, Vlassara H, Cerami A. Cachectin/tumour necrosis factor. Lancet 1:1122-6, 1989.
15. Wong GHW, Goeddel DV. "Tumour necrosis factor" in Human Monocytes M Zembala, GL Asherson, eds. Academic Press, New York, 1989, pp195-213.
16. Tracey KJ, Cerami A. Tumor necrosis factor, other cytokines and disease. Annu Rev Cell Biol 9:317-43, 1993.
17. Tracey KJ, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapuetic target. Annu Rev Med 45:491-503, 1994.
18. Durum SK, Oppenheim JJ. "Proinflammatory Cytokines and Immunity" in Fundamental Immunology, 3rd Edition, WE Paul, ed, Raven Press, New York, 1993, pp 801-30.
19. di Giovine FS, Mee JB, Duff GW. "Immunoregulatory Cytokines" in Therapeutic Modulation of Cytokines B Henderson, M Bodmer, eds. CRC Press, 1996 pp 38-60.
20. Wong GG, Clark SC. Multiple actions of interleukin 6 within a cytokine network. Immunol Today 9:137-139, 1988.
21. Ershler WB. Interleukin-6: a cytokine for gerontolgists. J Am Geriatr Soc 41:176-81, 1993.
23. Whittington R, Faulds D. Interleukin-2. Drugs 46:446-514, 1993,
24. di Giovine FS, Mee JB, Duff GW. "Immunoregulatory Cytokines" in Therapeutic Modulation of Cytokines B Henderson, M Bodmer, eds. CRC Press, 1996, pp 38-60.
25. Hanisch UK, Quirion R. Interleukin-2 as a neuroregulatory cytokine. Brain Research Reviews 21:246-84, 1996.
26. Michie HR, Eberlein TJ, Spriggs DR et al. Interleukin-2 initiates metabolic responses associated with critical illness in humans. Ann Surgery 208:493-508, 1988.
27. Merrill JE. Interleukin-2 effects in the central nervous system. Ann NY Acad Sci 594:188-199, 1990.
28. Nistico G, DeSarro G. Is interleukin 2 a neuromodulator in the brain? Trends Neurosci 14:146-150, 1991.
29. Smith RS. A Comprehensive Macrophage-T-Lymphocyte Theory of Schizophrenia. Medical Hypotheses 39:248-257,1992.
30. Smith RS, Maes M., The Macrophage-T-Lymphocyte Theory of Schizophrenia: Additional Evidence. Medical Hypotheses 45:135-141,1995.
31. Dinarello CA. Modalities for reducing interleukin-1 activity in disease. Immunology Today 14:260-4, 1993.
32. Dinarello CA, Gelfand JA, Wolff SM. Anticytokine strategies in the treatment of the systemic inflammatory response syndrome. J Am Med Assn 269:1829-35, 1993.
33. Burger D, Dayer JM. Inhibitory cytokines and cytokine inhibitors. Neurology 45(suppl 6):S39-S43, 1995.
34. Enayati P, Fong Y. Cytokine neutralizing strategies in experimental sepsis. Prog Clin Biol Res 388:295-306, 1994.
35. Paul WE, ed. Fundamental Immunology, 3rd Edition, Raven Press, New York, 1993.
36. Dinarello CA. Interleukin-1 and the pathogenesis of the acute phase response. New Engl J Med 311:1413-1418, 1984.
37. Guyton A, Hall J. Textbook of Medical Physiology, 9th Ed, Saunders, Philadelphia, 1994, pp 435-444.
38. Bullen JJ. The significance of iron in infection. Rev Infec Dis 3:1127-38, 1981.
39. Klasing KC. Effect of inflammatory agents and interleukin 1 on iron and zinc metabolism. Am J Physiol 247:R901-4, 1994.
40. Dinarello CA. Interleukin-1 and the pathogenesis of the acute phase response. New Engl J Med 311:1413-1418, 1984.
41. Brown ML, ed. Present Knowledge in Nutrition, 6th Ed. International Life Sciences Instit., Washington, 1990, pp 444-450.
42. Baumann H, Gauldie J. The acute phase response. Immunology Today 15:74-80, 1994.
43. Steel DM, Whitehead AS. The major acute phase reactants: C-reactive protein, serum anyloid P component and serum amyloid A protein. Immunology Today 15:81-88, 1994.
44. Tracey KJ, Cerami A. Tumor necrosis factor, other cytokines and disease. Annual Rev Cell Biology 9:317-43, 1993.
45. Annon. Muscle provides glutamine to the immune system. Nutrition Reviews 48:390-2, 1990.
46. Newsholme EA, Parry-billings M. Properties of glutamine release from muscle and its importance for the immune system. J Parenteral Enteral Nutr 14:63S-67S, 1990.
47. McCann SM, Lyson K, Karanth S. et al. Role of cytokines in the endocrine system. Ann NY Acad Sci 741:50-63, 1994.
48. Jones TH, Kennedy RL. Cytokines and hypothalamic-pituitary function. Cytokine 5:531-8, 1993.
49. Reichlin S. Neuroendocrine-immune interactions. New Engl J Med 329:1246-53, 1993.
50. Opp MR, Krueger JM. "Interleukin-1 involvement in the regulation of sleep." in Interleukin-1 in The Brain (Rothwell NJ, Dantzer RD, eds) Pergamon Press, Oxford, 1992, pp`151-69.
51. Van Cauter E, Linkowski P, Kerkhofs M et al. Circadian and sleep-related endocrine rhythms in schizophrenia. Arch Gen Psychiatry 48:348-56, 1991.
52. Clevenger CV, Russell DH, Appasamy PM, Prystowsky MB. Regulation of interleukin 2 driven T-lymphocyte proliferation by prolactin. Proc Natl Acad Sci 87:6460-4, 1990.
53. Mukherjee P, Mastro AM, Hymer WC. Prolactin induction of interleukin-2 receptors on rat splenic lymphocytes. Endocrinology 126:88-94, 1990.