Interleukin-6 : Catabolic Agent or Growth Factor?
THE PROTEIN in our muscles undergoes a continual process of synthesis and degradation. Athletes and weightlifters know that after a strenuous workout, muscle tissue is damaged and needs time to regenerate and be repaired. If we provide sufficient rest and adequate nutrition, the body will usually overcompensate and produce stronger and larger muscles.
Most analyses of strength training are concerned with two phases: the work phase where we apply physical stress to our muscles to cause microtrauma and resulting overcompensation, and the anabolic phase in which we seek to enhance protein synthesis. But there's a third phase, a period of breakdown and recovery, which is rarely discussed. We are told to rest and to do what we can to avoid cortisol, but very seldom is there any mention of the signal molecules which accomplish the work of bringing the body back to a state of homeostasis.
Weightlifters talk of "destroying" their legs in a squat workout; of loading the muscles with weight and stressing them until they are barely able to function. What are the mechanisms that permit the body to recover from such punishment? Is it possible to optimize recovery so that less tissue is broken down, and we get into the anabolic phase more quickly?
The essay that follows will deal with some very technical concepts. I'm including a glossary containing brief definitions for the scientific terms used. The purpose of such a technical essay is twofold: First, it introduces some basic ideas in cell biology that will enable a better understanding of exercise physiology. Once the basic concepts are learned, one can view this area of science not as a collection of disparate facts, but as a coherent system that runs on a logical -- but complicated -- basis. Secondly, by going into detail concerning the stages whereby the body detects damage, disposes of damaged tissue, and ultimately replaces or strengthens the affected tissue, we can identify areas where we can intervene with nutrition or chemical agents to reduce damage and enhance our muscular gains. Also, it may be possible to take advantage of this intimate knowledge to design training protocols that coincide with the catabolic and anabolic stages that follow exercise.
Cytokines and Interleukins
There are four types of signaling molecules in the body: neurotransmitters, endocrine hormones, autacoids and cytokines. Cytokines are soluble proteins which act non-enzymatically to regulate cell function. There are various types of cytokines, among them being interleukins, hematopoietic regulators, interferons, growth and differentiation factors and chemotactic polypeptides. Interleukins (abbreviated IL) are cytokines that are produced by leukocytes (white blood cells) and that function during inflammatory responses. They may also be produced by other types of cells. Typically, interleukins have the twin properties of pleiotropy and redundancy. Pleiotropy means that an interleukin may have several different effects, depending on the environment and the tissue acted upon. Redundancy in this case refers to the ability of other cytokines (interleukins or not) to produce some of the same effects as the interleukin being studied. This redundancy can be due to the fact that receptors for interleukins often share common subunits, or it may also be caused by identical effects on transcription factors or on the DNA itself.
As of October 1998, eighteen different ILs have been described. We'll be focusing on interleukin-6 (IL-6), which has some special properties that make it interesting to bodybuilders. For those who might be curious, here is a brief survey of all the interleukins:
Figure 1.IL-6 molecule
Interleukin Description
IL-1 An inflammatory cytokine. One of the first cytokines to be secreted following trauma, infection, etc. Induces IL-6.
IL-2 Secreted by Type 1 T-helper cells (Th1) of the immune system. Stimulates cell-mediated (as opposed to antibody-mediated) immunity. Generally a beneficial cytokine. IL-2 levels decline with age, but are upregulated by DHEA.
IL-3 Growth factor for hematopoietic cells. Acts in a similar fashion as granulocyte-macrophage colony-stimulating factor (GM-CSF). Secreted by activated T lymphocytes, it induces formation of macrophages, neutrophils, etc. Also induces secretion of immunoglobulin from B cells.
IL-4 Anti-inflammatory cytokine. Related to IL-13. Released by activated T cells, it initiates the humoral response (antibodies).
IL-5 A B-cell growth and differentiation factor; also stimulates eosinophil precursor proliferation and differentiation. Secreted by activated T cells.
IL-6 Pro- (and sometimes anti-) inflammatory cytokine. Pleiotropic. The subject of this article. Main signal of cellular injury, and main mediator of the body's response to injury. Most important stimulator of acute phase proteins. Has an important role in hematopoiesis. Produced by a variety of cells.
IL-7 Growth factor produced by a number of different cells. Unlike other interleukins, IL-7 in not redundant, i.e. its function can not be duplicated by other cytokines. It is required for lymphocyte development.
IL-8 Pro-inflammatory. A chemokine. Can be induced by IL-1 and lipopolysaccharide from bacteria. Produced by many different cells.
IL-9 Cytokine produced by T cells, particularly when mitogen stimulated, that stimulates the proliferation of erythroid precursor cells. May act synergistically with erythropoietin. Synergizes with IL-4 to produce immunoglobulins.
IL-10 Anti-inflammatory. Produced by Th2 cells, plus some B cells and monocytes. Stimulates growth of stem cells and thymocytes. Stimulates B and T cell development. Suppresses cytokine production by macrophages.
IL-11 Pleiotropic cytokine originally isolated from bone marrow. Stimulates B cell maturation, and production of erythrocytes (red blood cells) and megakaryocytes. Synergizes with IL-3. Induces synthesis of acute-phase proteins in the liver.
IL-12 Formerly known as Natural Killer Cell Stimulatory Factor (NKSF). Produced by monocytes, macrophages, B cells, NK cells. Acts synergistically with IL-2 to transform T cells into cytotoxic T lymphocytes (CTLs). Stimulates the proliferation of activated T cells and NK cells and induces them to produce interferon-gamma.
IL-13 Anti-inflammatory. Related to IL-4. Produced by activated Th2 cells. Inhibits IL-6. Stimulates antibody production.
IL-14 A high molecular weight B lymphocyte growth factor. One of the least researched cytokines.
IL-15 Anabolic for skeletal muscle. IL-15 receptor contains some sub-units with the IL-2 receptor.
IL-16 Pro-inflammatory. Formerly called Lymphocyte Chemoattractant Factor.
IL-17 Pro-inflammatory. Produced by T cells. Activates NF-kappaB.
IL-18 Pro-inflammatory. Induces the cytokine interferon-gamma.
Interleukins and the Acute Phase Reaction
Fig. 2. Top mouse was continuously exposed to IL-6. Bottom mouse received antibodies against IL-6. From DeBenedetti1997.
EXERCISE modulates the immune system. Following even moderate exercise, there is an elevation in the number of neutrophils, the most common type of white blood cell (Boyum1996, Cannon1994, Tidball1995).
After acute or short-term exercise, the total number of lymphocytes increases, but if the exercise is intense and of long duration the number of lymphocytes decreases (Pedersen1997). A lack of glutamine resulting from exercise stress can impair the ability of lymphocytes to proliferate and to function (Sharp1992, Rohde1998).
Prolonged low intensity exercise may lower levels of interleukin-6 in the blood (Boyum1996), while intense or eccentric (negative) exercise causing muscle damage induces a dramatic rise in this cytokine (Bruunsgaard1997, Weinstock1997, Ullum1994).
In short, intense exercise increases cytokines which may act to break down muscle, while extensive exercise decreases cell- mediated immunity (i.e. the ability of Natural Killer cells, cytotoxic T lymphocytes, and phagocytes to eliminate potentially harmful cells and materials).
Massage therapy has been shown to increase cell-mediated immunity (Ironson1996), so there may be some benefits in combining massage with some forms of exercise.
The immune system
The human immune system is a network of active and passive defenses against substances and cells that would harm the body. It includes innate immunity from barriers like the skin, body temperature, pH (acidity) of the stomach, the inflammatory response and the action of phagocytic cells. It also includes acquired immunity, which is usually based on recognition and response to an antigen. This generally involves white blood cells called lymphocytes. There are two kinds: T cells (from the thymus) and B cells (from the bone marrow). Acquired immunity may be humoral, meaning it involves substances like antibodies and cytokines that are dissolved or suspended in the blood, or it may be cell-mediated, involving the cytotoxic activity of specialized cells.
Because the effects of exercise on the immune system do not involve antigens, such immune activity is fundamentally different from what you might read about in a text on immunology.
The Acute Phase Response
PARTS of the immune system are depressed following a workout. However, this is not to say that the body is defenseless. There is a "rapid deployment" system called the acute phase response that kicks in after trauma, and exercise is generally interpreted by the body as trauma. Exercise subjects the body to oxidative stress, and that generates reactive oxygen species and other free radicals that act as alarm molecules. Also, the body can sense potentially dangerous changes in osmolarity (e.g. swelling), hyperthermia (heat), hypoxia (oxygen starvation), pH (acidity) of the blood, ionic contents of cells, and a variety of other conditions.
Once initiated, the response is in the form of a cascade. Local to the injury there is acute inflammation and blood clotting. Systemically there is fever, leukocytosis (increased white blood cells), increased levels of hormones like cortisol, and in particular a major increase in synthesis of proteins called acute phase proteins (ACPs). Let's look at this process in more detail.
Initialization
During exercise, free radicals known as reactive oxygen intermediates (ROIs) and reactive nitrogen intermediates (RNIs) are formed. Additionally other reactive intermediates such as carbonyls may be produced. All these free radicals can signal and in some cases activate cells of the immune system.
When intense exercise causes damage to cells, the contents of the breached cell enters the surrounding lymph. This also has the effect of signalling that there has been damage.
Monocytes are white blood cells with a single nucleus that are formed in the bone marrow. When they arrive in the tissues of the body they may differentiate (mature) into macrophages, and lose some of their motility (ability to move independently). Muscle tissue contains a number of macrophages, and these are the first immune cells to react to exercise trauma. When a macrophage is activated, it undergoes a "respiratory burst" of oxidation, which produces even more ROIs, thus extending the signal to surrounding cells. Macrophages also secrete signal molecules like IL-8 which act as chemokines to attract other immune cells, in a process called chemotaxis.
Prostaglandins are secreted by macrophages as well. These, plus some metabolic byproducts of exercise like lactic acid, physical changes involved in pumping the muscle, and the effects of the first immune phenomena just described, combine to initiate inflammation in the effected muscles.
Neutrophils in the blood sense the alarm molecules and chemokines, and race to the defense of the injured tissue. The inflamed blood vessels are more permeable, and in a process called extravasation the neutrophils escape from the bloodstream, enter the muscles, and home in on the damage. They in turn are activated, undergo a respiratory burst, and begin secreting cytokines.
Cytokines
The first cytokines to be released as a result of exercise are the "pro-inflammatory" substances interferon-gamma (IFN-gamma), tumor necrosis factor (TNF) and interleukin-1 (IL-1). Also the chemokine IL-8 is released. IFN-gamma, TNF and IL-1 have a number of different effects on the body. They travel through the bloodstream and stimulate the liver to synthesize acute phase proteins like C-reactive protein, serum amyloid A and fibrinogen. They influence complement, which is yet another factor in the immune system, and kinins, which can produce vasodilation, pain, and may make you lose your lunch in the squat rack. They cause body temperature to increase. Most important for this article, all three act on T lymphocytes to cause them to secrete interleukin-6.
IFN-gamma, TNF and IL-1 all have the reputation of being catabolic cytokines which will reduce muscle mass. For example, IL-1 activates the enzyme "branched-chain alpha-keto acid dehydrogenase" to oxidize amino acids in the muscles (Cannon1991). However as we'll see below, at least part of the wasting effect may be mediated by IL-6, so that if the effect of IL-6 is blocked some of the catabolism is stopped.
T cell activation
A second part of the cytokine cascade derives from activated lymphocytes. As we've mentioned, under normal exercise conditions, immune cells are not activated by antigens. There are alternative methods by which they can be activated. For example, lymphocyte proliferation can be artificially stimulated with a chemical that increases the level of glutathione, an antioxidant (Berridge1997). Also it is known that reactive oxygen intermediates like hydrogen peroxide ( H2O2 ) can activate the nuclear transcription factor NF-kappaB. So there is good reason to expect that the reduction/oxidation changes resulting from exercise may result in T cell activation.
Also it is known that certain cytokines can activate lymphocytes. For example, IL-1 was originally called "Lymphocyte Activating Factor."
B lymphocytes are involved in antigen-based antibody formation, so although they also secrete some cytokines we won't consider them further. T cells differentiate under the influence of cytokines into cytotoxic T lymphocytes and T helper (Th) cells. We need only consider the latter. Th cells in turn differentiate into type 1 and type 2 T helper cells (Th1 and Th2). It is the Th2 cells that produce the bulk of the interleukin-6, although macrophages also produce it, and even muscle cells seem to produce some under stress. We'll cover IL-6 in detail below.
Termination of the acute phase
Cytokines and acute phase proteins have a brief half- life in the body, so even without anti-inflammatory signalling this phase would inevitably end. However a number of substances produced by the body have the effect of bringing it to a conclusion more quickly.
As we all know, cortisol is secreted as a result of exercise. A product of the adrenal glands, cortisol is a member of a class of compounds called glucocorticoids. We normally think of glucocorticoids as being catabolic, but they also has the effect of inhibiting the synthesis of all acute phase cytokines. Since many of those cytokines are catabolic, this is actually an anti-catabolic action of cortisol. To put this in another way: if you are successful in limiting cortisol production after a workout, you might find an increased level of cytokines, and thus no net prevention of muscle loss!
Cytokines sometimes have soluble receptors. One way these are produced is from membrane receptors that are cleaved and "shed" from cells. The receptors then circulate in the blood. Soluble receptors for IL-1, IL-4 and TNF have the effect of binding to and thus deactivating their cytokines. You might say they "mop up" the cytokine. The production of these soluble receptors is a second way in which the body limits the acute phase. On the other hand, soluble receptors for IL-6 have the opposite effect: they can cause IL-6 metabolic effects on cells with incomplete receptors that normally wouldn't be effected.
A protein called IL-1 receptor antagonist (IL-1Ra) binds to IL-1 receptors, blocking the effect of IL-1. IL-1Ra is secreted from cells upon stimulation by TNF, and its production is enhanced by IL-10 and IL-4. As levels of these last interleukins rise, IL-1 declines.
IL-10, IL-4 and IL-13 are anti-inflammatory cytokines. They inhibit the production of inflammatory cytokines and also reduce induction of cyclooxygenase-2 (COX2), an enzyme involved in inflammation which is the target of drugs like aspirin. Whereas IL-1 and TNF are produced early in the acute phase response, the anti-inflammatory cytokines come from activated T cells, so they are a way in which the body gracefully concludes the acute phase.
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IL-6
INTERLEUKIN-6 stands out among the interleukins in several ways. It is the main signal of tissue damage in the body (Sehgal1995). Although IL-1 and interferon initiate the synthesis of some acute phase proteins by the liver, IL-6 stimulates the liver to produce a larger and more complete set of these proteins (Hilton1992, Baumann1987). IL-6 is thought by many investigators to be the main factor in cachexia -- the wasting syndrome that accompanies AIDS, cancer, and some autoimmune diseases. Yet IL-6 is also a growth factor, intimately involved in the production of new cells, including new muscle cells.
A better understanding of the pleiotropic roles of interleukin-6 should provide insight into methods of improving physical development through training, nutrition and supplementation.
The IL-6 family of cytokines
IL-6 belongs to a family of physically similar or "homologous" cytokines, including Leukemia Inhibitory Factor (LIF), Ciliary Neurotropic Factor (CNTF), Granulocyte-Colony Stimulating Factor (G-CSF), IL-11, Oncostatin M (OSM), and Cardiotropin-1 (CT-1). IL- 6 type cytokines feature four anti-parallel helices, arranged as shown in Figure 1.
Receptors for IL-6 family cytokines are mulitimeric, having a specific component for binding with the cytokine, plus a transmembrane transducer protein called gp130 for delivering the signal to the nucleus of the cell. For example, the LIF receptor is composed of a gp130 molecule plus a specific component called LIFR-beta. IL-6 receptor is a trimer, with two gp130 molecules, plus a specific component called IL-6R-alpha. When IL-6 first contacts the cell, it binds with IL-6R-alpha. Then the gp130 molecules dimerize and bind with it to form the ligand-receptor complex.
While all this may appear a bit technical, study of the receptors and how they are bound tells us much about the actions of these cytokines. By means of this knowledge we can often block their effects.
Signal transduction
Once the IL-6 receptor complex is assembled and bound, chemicals within the cells called Janus kinases (JAK) phosphorylate the amino acid tyrosine on the gp130 molecules. We have an effective tyrosine kinase inhibitor (genistein) that can block this process. We'll return to genistein in the section on IL-6 blockers, below.
The phosphotyrosines link up with a substance previously termed "acute phase response factor" (APRF), but which is now called STAT3 (for "Signal Transducer and Activator of Transcription"). STAT1 and STAT3 become phosphorylated and dimerize. Then these dimers travel to the nucleus of the cell. Meanwhile the IL-6/IL-6R-alpha combination is taken into the cell ("endocytosed") and is broken down and destroyed. The gp130 units are recycled.
The STAT dimers bind with IL-6 response elements which then activate gene transcription factors.
NF-IL-6 (Nuclear Factor IL-6) is a member of the C/EBP (CAAT/Enhancer Binding Protein) family of transcription factors. It is almost undetectable in normal circumstances, but when cells are stimulated with IL-6 it is produced abundantly. C/EBP regulates fat tissue. It increases differentiation from pre-adipocytes to adipocytes, activates the glucose transporter GLUT4, etc. In short, it makes you fat. When adipose tissue is treated with TNF -- which reduces fat -- C/EBP is reduced, but NF-IL6 increases. It seems that the ratio of C/EBP to NF-IL-6 is a determinant of fatness. Both IL-6 and LIF are known to drastically reduce fat, so the activation of NF-IL-6 may be one of the mechanisms of that fat reduction.
STAT3 can also bind to the IL-6 response element of the junB gene (JRE-IL6).
Apart from the JAK/STAT pathway, there is a second pathway from the IL-6 receptor to the nucleus. It involves a protein called ras, and Mitogen Activated Protein Kinase (MAPK).
As a result of the alternate pathways, a variety of transcription factors can be activated, including AP-1 (Activator Protein-1) and NF-kappaB (Nuclear Factor kappa B).
NF-kappa B
NF-kappaB deserves special mention. The name derives from its discovery in B cells expressing kappa immunoglobulin. Subsequently it was found that NF-kappaB exists in nearly all mammalian cells. It regulates inflammation, immune reactions and acute phase response, and it is generally bad news for athletes. Elderly people and people with AIDS or chronic inflammation may have NF-kappaB almost permanently activated, which accounts for some of the tissue loss and poor health in those groups. On the other hand, NF-kappaB regulated genes encode hematopoietic growth factors, which can be useful to athletes.
Nuclear Factor kappa B
NF-kappaB is activity is low is a normal cell, due to an inhibitor named I-kappa-B. IL-1 and TNF act to degrade I-kappa- B, and by this means NF-kappaB is activated. As a result of transcription regulated by NF-kappaB, many cytokines -- including Il-6 -- are expressed. This is one way that IL-1 and TNF induce the secretion of Il-6. NF-kappaB can also be activated by reactive oxygen intermediates, and by IL-6 as described in the previous section.
There are several effective methods of inhibiting NF-kappaB, some of which will be described below.
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Effects of IL-6
MYOGENESIS -- the creation of new muscle tissue -- occurs when muscle satellite cells (also called sarcoplasts) or myoblasts (also called sarcoblasts) are activated. Often the terms "myoblast" and "satellite cells" are used interchangeably. Once activated, these cells proliferate, and then differentiate, and finally fuse with other cells to form myotubes or to join existing muscle fibers. The signal for these cells to proliferate is Hepatocyte Growth Factor (HGF). HGF is induced by heparin, which is liberated from the basal lamina of muscles when they are damaged. It is also induced by interferon-gamma, and is very potently induced by prostaglandin E2. All of these substances appear as a result of trauma to the muscle. In addition to activating the myoblasts, HGF increases their motility, so that they can migrate to the site of damaged muscle.
This same trauma results in the expression of IL-6, LIF, and Fibroblast Growth Factor (FGF). These three act as growth factors (yes, in this case IL-6 is a growth factor), increasing the proliferation of myoblasts. See Figure 3: response of IL-6 and LIF to muscle injury (source: Kurek1996). LIF is a stronger inducer of proliferation than IL-6, and whereas the effect of IL-6 is short-lived, a brief exposure to LIF will result in proliferation over an extended period. Injections of LIF have been suggested as a therapy for muscle trauma and disease (Kurek1996).
When cells divide, the telomeres at the end of their chromosomes shorten. Since the telomeres become shorter with each division, this sets a limit (the "Hayflick limit") on the number of times that a cell and its descendent cells can divide. This is particularly important in germ cells like myoblasts. An enzyme named telomerase can prevent the telomeres from shortening. Certain cytokines, including IL-6, can induce telomerase, hence increasing the number of times a cell can divide (Engelhardt1997). This appears to be a unique contribution made by IL-6 to the muscle regeneration system. IL-6 also has a similar effect in hemopoietic tissue.
Effect on Fat
Experiments on mice that were reported in 1989 and 1990 showed LIF inhibits the action of lipoprotein lipase (LPL), which is instrumental in uptake of fatty acids by adipose tissue (Hilton1992). A "dramatic and rapid loss of virtually all subcutaneous and abdominal fat" was reported. More recently, it has been shown that while administration of recombinant IL-6 to mice reduces LPL, it has almost no effect on fat reduction in mice (Fujita1996).
We've previously mentioned that IL-6 activates a regulator of fat tissue called NF-IL-6. NF-IL-6 is actually a repressed transcription factor which is normally inhibited. Signalling from IL-6 through the MAP kinase pathway overcomes the inhibition (Akira1995). In this way, while IL-6 may not be as successful at blocking fat uptake as LIF, it may decrease body fat by slowing the maturation of adipocytes.
Effect on Muscle
There are three main proteolytic pathways in skeletal muscle: cathepsins functioning in the lysosome, calpain proteases in the cell's cytosol, and the ATP-ubiquitin (Ub) pathway. IL-6 acts to destroy muscle through the cathepsin and ATP-Ub pathways. Fujita et al. showed that mice inoculated with a cancer (adenocarcinoma) developed high levels of IL-6 after 11 days: while untreated control mice had a level of 7.9 pg/ml of IL- 6, inoculated mice had an average of 1,142 pg/ml (Fujita1996). These inoculated mice had cathepsin B levels 236% higher, and cathepsin B levels 826% higher than controls. Tsujinaka et al. showed that in transgenic mice carrying DNA for human IL-6, treated mice had cathepsin B levels 20 times higher than controls (Tsujinaka1996).
IL-6 shortens the half-life of proteins in the myotubes that make up muscle fibers. It has been demonstrated that mRNA levels of proteosomes, which are involved with the ATP-Ub pathway, are increased by IL-6 (Ebisui1995, Tsujinaka1996). Strangely, TNF, which is often named as the main culprit in cachexia (wasting syndrome), has not been shown to have this effect. In fact, several studies have failed to show a direct effect by TNF on muscle proteolysis (reviewed in Fujita1996). Therefore it seems that the proteolytic action of TNF may actually be mediated through IL-6. In other words, without IL-6, TNF would not destroy muscle (although it would reduce fat). Therefore, IL-6 appears to be the primary agent in muscle wasting.
IL-6 is a catabolic agent in many disease states (Papanicolaou1998). It is present in rheumatism and other autoimmune type diseases, and is responsible for joint deterioration and muscle loss. DeBenedetti et al. found that transgenic mice with human IL-6 had stunted growth, attaining only about half the size of normal mice (Figure2). They also showed that in humans as well as mice, there is a negative correlation between IL-6 and IGF-1. In other words, the more IL-6 in the body, the less IGF-1. This relationship was unique to IL- 6: TNF and IL-1 were not correlated with IGF-1 (DeBenedetti1997).
In summary, the effects of IL-6 are mostly harmful for athletes. It plays beneficial roles in resisting infection, stimulating the acute phase response in case of trauma, and in hematopoiesis and production of stem cells. However, excessive IL-6 resulting from exercise or chronic inflammation will destroy muscle tissue and reduce IGF-1.
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Manipulation of IL-6
Now that we know the actions and effects of interleukin-6, let's consider ways to manipulate IL-6 secretion.
In the unlikely event that we'd want more IL-6, the method is obvious: just exercise. Any exercise that causes trauma to the muscles would suffice. If we want to start an acute phase response without the temporary immune suppression caused by exercise, there are herbs like Echinaceae and Rudbeckia speciosa that contain polysaccharides the body mistakes for bacteria, so that they can initiate an immune response (Bukovsky1995).
For inhibition of IL-6 and its effects there are many options. We'll first cover nutrition and supplements, and then drugs. Not all the options mentioned will be suitable for athletes; the goal here is to compile a comprehensive list from which people can choose according to their needs.
Nutrition and Supplements
Caloric restriction is perhaps the simplest method of reducing IL-6 (Volk1994). This is a technique employed by life- extensionists. It might have some application to dieting athletes, providing they don't use weight-loss drugs.
Oils and fatty acids.
oEicosapentaenoic acid (EPA) supplementation significantly reduced IL-6 ecretion from mononuclear cells in patients with cancer (Wigmore1997).
oSupplementation with docosahexaenoic acid (DHA) and EPA reduced production of IL-1, IL-6, TNF and IL-2 by mononuclear cells in normal individuals and in patients with Rheumatoid Arthritis and with Multiple Sclerosis (Calder1997).
o The fatty acids gamma linolenic acid (GLA), EPA and DHA reduce serum IL-1, IL-2, IL-4, IL-6, TNF alpha and IFN-gamma in cancer patients. Three months after cessation of fatty acid supplementation cytokine values returned to normal (Purasiri1994).
o In human endothelial cells, DHA decreased secretion of IL- 6, IL-1, IL-4, IL- 8 and TNF (DeCaterina1994).
o Blackcurrant seed oil rich in GLA reduced production of IL- 1 beta, TNF alpha IL-6 and PGE2 (Watson1993).
Sources of GLA: evening primrose oil, borage seed oil, blackcurrant seed oil.
Sources of EPA and DHA: fish oils (e.g. cod liver oil, salmon oil, etc.).
Lactoferrin (found in milk) reduces IL-6 (Mattsby1996).
Estrogen and androgens reduce IL-6 and block NF-kappaB. Therefore, foods like soy which are estrogenic and supplements like androstenedione would be expected to have a similar effect.
Since one of the signal pathways from the IL-6 receptor depends on tyrosine kinase, genistein, which is an effective tyrosine kinase inhibitor, should block it. Genistein is a component of soy, and can be purchased in purified form.
Zinc induces Heat Shock Protein HSP-70 and reduces cytokines and apoptosis (Klosterhalfen1997).
Antioxidants. Since antioxidants provide some of the initial signals in the acute phase response, and since NF-kappaB can be directly activated by reactive oxygen intermediates, antioxidants can prevent secretion of IL-6 and the effects of NF-kappaB transcription.
o Vitamin E supplementation (400 units twice per day) almost completely eliminated increased secretion of Il-6 in athletes following three 15 minute sets of downhill running (Cannon1991).
o L-ascorbic acid inhibits secretion of IL-1 and IL-6 (Tebbe1997).
o Black tea extract lowers concentrations of IL-6 (Amarakoon1995).
o Melatonin reduces oxidative stress, improves immune function. etc. (Reiter1997).
o Since expression of IL-6 mRNA is dependent on NF-kappaB binding to the IL-6 gene, supplementation with the antioxidant N-acetyl-L-cysteine (NAC) can block the process (Shibanuma1994).
o A number of experimental antioxidants have been employed in studies of NF-kappaB inhibition. They include glutathione, NADPH, pyrrolidine dithiocarbamate (PDTC), butylated hydroxyanisole (BHA), and various forms of superoxide dismutase.
Since IL-1, IFN-gamma, and TNF induce IL-6 production, any substances that inhibit them will usually have the effect of inhibiting Il-6.
NF-kappaB can be inhibited by nitric oxide (NO). One substance that induces NO is the amino acid arginine.
Aspirin and salicylate inhibit NF-kappaB. Also salicylate inhibits protein kinase activity, and so would prevent signalling by IL-6 via tyrosine kinase (Beauparlant1996). Since methyl salicylate is a common ingredient of ointments for sore muscles, this raises the possibility that a topical application could be effective against IL-6.
There is a negative correlation between dehydroepiandrosterone sulfate (DHEAS) and IL-6 in the blood (Straub1998). Therefore supplementation with DHEA will reduce IL-6.
Drugs for IL-6 reduction
Since IL-6 is a factor in many diseases, a number of drugs and pharmaceutical techniques have been investigated for lowering IL- 6 levels. Some of the substances mentioned below are experimental or unapproved.
Glucocorticoids like dexamethasone block transcription factors NF-kappaB and AP-1 (Brattsand1996). Unfortunately they are also catabolic to muscle, and so are of little use to the athlete, except in case of injury.
RU486 (mifepristone) can block NF-kappaB induced by TNF, although not as well as glucocorticoids (Beauparlant1996). It has the advantage that it also blocks glucocorticoid receptors, but unfortunately the receptors soon upregulate.
The immunosuppressant drugs FK506 and cyclosporin A will suppress T cells, but this would be an insane way to inhibit IL-6, due to the side effects.
Anti-inflammatory cytokines like IL-10, IL-4, IL-13, and Transforming Growth Factor beta (TGF-beta) will inhibit synthesis of IL-6 and other inflammatory cytokines. IL-10 also enhances synthesis of IL-1 receptor antagonist, downregulates TNF receptors and inhibits T cell proliferation (Koj1998, Xing1997, Dokter1996).
Soluble cytokine receptors and receptor antagonists are effective against IL-1 and TNF, which induce IL-6. Unfortunately, the IL-6 soluble receptor only increases the effect of IL-6. Enbrel, a soluble receptor for TNF made by Immunex, will be on the market soon for treatment of rheumatoid arthritis and similar inflammatory conditions.
Rolipram, an antidepressant sold in Europe by Schering, is also very effective at inhibiting TNF, and so has an indirect effect on IL-6.
Tenidap, a new anti-rheumatic drug, showed a great deal of promise against cytokines, but the FDA decided not to approve it because of problems with proteinuria (protein in the urine). This side effect may make it unsuitable for athletes. It is available from Europe (Breedveld1994, Bondeson1996).
Polymyxin B administration results in a prompt reduction in interleukin-6 levels in burn patients (Cone1997).
For women, medroxyprogesterone acetate has reduced IL-6 in breast cancer patients. Reduction was correlated with plasma levels of MPA, not dosage (Yamashita1996).
Use of a monoclonal antibody against CD-54 (ICAM-1) reduced IL-6 in rheumatoid arthritis (RA) patients (Schulze1996).
Antibodies against TNF have been used to reduce IL-6 (Fekade1996).
Indomethacin reduces Il-6 by inhibiting prostaglandin E2 (Hinson1996).
Tyloxapol, a potent anti-oxidant used in the treatment of cystic fibrosis and chronic bronchitis, inhibits NF-kappaB and IL-6 (Ghio1996).
The anti-rheumatic drug minocycline decreases serum levels of IL-6 (Kloppenburg1996).
The anti-rheumatic drug tepoxalin inhibits the production of IL-2, IL-6 and TNF alpha and inhibits activation of NF- kappaB (Ritchie1995).
Pentoxifylline is a methylxanthine derivative that acts as a phosphodiesterase inhibitor and is prescribed to improve capillary flow. It inhibits TNF and IL-6 and counteracts the respiratory burst of phagocytes that produces free radicals (Lundblad1995), Koj1998, Mandell1995).
Torbafylline, a xanthine derivative that suppresses TNF, has been used with some experimental success in the treatment of cachexia (Sinha1995).
The sex hormones estrogen and testosterone block IL-6 (Bellido1995, Vaananen1996, Stein1995). In fact, it seems that nearly any steroid inhibits IL-6: estrogen, testosterone, DHEA, glucocorticoids, and probably most androgenic/anabolic drugs.
Angiotensin Converting Enzyme (ACE) inhibitors decrease the levels of angiotensin II or limits its action, thereby interfering with the permissive effect of Angiotensin on IL-6 (Klahr1998).
Antibodies that destroy IL-6 receptors are effective at preventing muscle proteolysis caused by IL-6 (Fujita1996).
Conclusion
EXERCISE activates the immune system, which then cycles through an abbreviated version of the acute phase response. Damage to muscles results in IL-6 secretion, which signals the body to produce acute phase proteins. Depending on the amount of muscle damage, the acute phase response will terminate sooner or later, by the action of cortisol and anti-inflammatory cytokines.
IL-6 is the main mediator of muscle wasting. It may have some beneficial actions at the onset of the acute phase response, but chronically high IL-6 levels must be avoided for good health and optimum muscular development. We have a number of ways to accomplish that, from the simple use of antioxidants to specially designed antibodies. Through the use of these agents in coordination with training activity, we can effectively reduce the unnecessary muscle breakdown that normally follows intense exercise.
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