Interleukin 6, a comprehensive guide to why it is so important to health

In this article we are going to see what is interleukin 6 (IL6) and why it is so important for the health.

Overproduction of IL-6 has been described as a harmful factor related to the pathogenesis of chronic processes, such as autoimmunity, rejection transplant organs, rheumatoid arthritis and congestive heart failure, among others.

Different studies indicate that the overproduction of interleukin 6 or IL-6 is associated with various inflammatory and autoinmune diseases ,such as arthritis, multile sclerosis or osteoporosis.

IL-6 is essential for the regulation of immune processes, although overproduction of cytokines leads to inflammation and disease (such as rheumatoid arthritis, Chron’s disease…). As a result, this cytokine must be regulated by controlling the duration and magnitude of the response (Kishimoto, 2006).

This cytokine has a dual effect, at certain levels it acts as a defense mechanism but the chronic inflammation it acts as a proinflammatory factor. IL-6 levels correlate with severity of sepsis and mortality (Hack et al., 1989). During acute inflammation, leukocytes are recruited, mainly neutrophils.When inflammation resolves, the recruited leukocyte population changes mainly from neutrophils to monocytes. This transition is regulated by IL-6. Another of the functions it performs is the activation and control of neutrophil infiltration (McLoughlin etal., 2003).

These data show that IL-6 works more as an anti-inflammatory cytokine than a proinflammatory cytokine.

¿What is interleukin 6?

IL-6 is a pleiotropic cytokine that can perform its functions endocrine, paracrine or autocrine in various tissues. It is mainly involved in inflammation and in the response to infections, although it has been described that it also plays an important role in the regulation of metabolism, regeneration and neuronal processes .

¿Where it is produced?

IL-6 is produced and secreted by various cell types such as monocytes, macrophages, T and B Lymphocytes, fibroblasts, endotelial cells, synovicytes, glial cells, adipocytes, and intestinal epitelial cells..

In summary, it is produced and secreted by cells of the immune system, such as monocytes and macrophages , but it is currently known that it can be produced and secreted by other cell types. In the last decade, adipose tissue and skeletal muscle, have become relevant as the main IL-6 producing and secretory organs in non-inflammatory conditions. Various studies shows that IL-6 would be involved in the control of body weight and metabolism ( particulary in functions related to insulin).

¿What is cytokine?

In the strict sense of the word, a cytokine is a molecule produced by one cell and has an effect on another ,in general they have been considered as growth factors and hormones of the inmune system and hematopoietic (Ozaki and Leonard, 2002).
Despite the complexity and diversity existing between cytokines, it has been posible to establish some general characteristics, which, although there are exceptions, help to define what factors can be considered cytokines, differentiating them from other types of soluble mediators such as hormones. Cytokines are proteins generally secreted, of low molecular weight and that are produced again in response to an immune stimulus, and their secretion is a brief event.

Biological properties of IL-6 cytokines:

Induction of proteins in the acute phase
Stimulation of hematopolesis
T cell activation
Stimulation of the proliferation and differentiation of T cells
Stimulation of B cell differentiation
Stimulation of NK cell activity
Regulation of adhesión molecules and chemotaxis
Regulation of osteoclast activity

Some studies:

In 1994 it was discovered that cytokines from the IL-6 family use tyrosine-kinases from the Jano kinase family (JAK)and transcription factors of the family of signal transducers and activators of transcription (STAT) as the main mediators of signal transduction (Heinrich et al., 2003; Lutticken et al., 1994; Stahl et al., 1994) a feature they share with interferons and other families of cytokines and growth factors.

Subsequent studies have shown that these cytokines also play a role in exercise-mediated metabolic changes as well as metabolic changes due to adaptation to exercise training. Of all the myokines that muscle produces during muscle contraction, IL-6 is the most abundant (Febbraio and Pedersen, 2002; Perdersen et al., 2001; Steensberg et al., 2000).

The IL-6 cytokine was the first myokine discovered to secrete into the bloodstream in response to muscle contraction (Pedersen and Febbraio, 2008; Steensberg et al., 2002).

Furthemore, functional and structural studies suggest that IL-6 forms a hexameric signaling complex containing two IL-6 molecules, two of IL-6R and two of gp130 (Boulanger et al., 2003). One of the main regulators of cytokine signaling is the existence of soluble receptors (Scheller et al., 2011). The soluble form of IL-6R (slL-6R) binds IL-6 with an affinity comparable to that of membrane bound IL-6R (mIL-6R). This receptor is generated by limited proteolysis of the transmembrane form or by alternative splicing of the IL-6R mRNA.

Unlike most soluble receptors cytokine and growth factors, sIL-6R not only binds to its ligand (IL-6), but the IL-6 / sIL-6R complex can also bind and activate gp130 (Scheller and Rose-John, 2006), which is found on the surface of practically every cell in the body. Thus, although IL-6R expression is restricted to a few cells, the existence of the soluble form allows cells that do not express IL-6R to respond to IL-6. This mechanism is known as trans-signaling (Assier et al., 2010; Mackiewicz et al., 1992; Peters et al., 1998; Rose-John and Heinrich, 1994)

¿Why it is important the interleukin 6?

IL-6 is a key signal in the transition from the innate initial response to infection to the adaptive immune response and plays an important role in regulating the passage of native T cells to suppressor cells (regulatory T) or activator (T helper). IL-6 has been described to modulate the balance between Th1 andTh2 cells. It promotes the differentiation of Th2 cells and inhibits the differentiation of Th1 cells. It also blocks the activity of regulatory T cells and promotes the development of helper 17 (TH17) T cells (Bettelli et al., 2006) that are implicated in the development of states of chronic inflammation and autoimmune diseases.

Inflammation is a complex defense mechanism in which leukocytes migrate from the vasculature to damaged tissue to destroy agents that potentially cause tissue deterioration. Furthermore acute inflammation is a beneficial limited response , while chronic inflammation is a persistent phenomenon that will lead to tissue damage. In an inflammatory situation, several signals are produced, among them IL-6 is the one that is first detected in serum and is responsible for producing fever and the acute phase response in the liver (Chai et al., 1996; Kopfet al., 1994).

The main source of IL-6 production are monocytes and macrophages during acute inflammation and T cells during chronic inflammation.

IL-6 is the main stimulator of the production of most of the acute phase proteins in the liver (Gauldie et al., 1987), which are a set of plasma proteins with concentrations increasing (positive acute phase proteins) or decrease (negative acute phase proteins) in inflammatory situations.

The liver is a very important organ. We also produce large amounts of serum proteins, including albumin, acute phase proteins, and clotting factors such as fibrinogen. Furthermore, it is the main detoxifying organ of the body and is involved in the elimination of xenobiotics by metabolic conversion and biliary excretion and in the conversion of ammonia to urea (Meshkani and Adeli, 2009).

Although IL-6 is often associated with inflammation and pathological states,it is a factor that also contributes decisively to normal brain function . In this way, IL-6 plays an important role in fever induction (Chai et al., 1996; Schobitz et al., 1995), stimulates the adrenal pituitary hypothalamic axis (Girotti et al., 2012), is involved in emotional behavior (Armario et al., 1998; Butterweck et al., 2003), in pain (Murphy et al., 1999; Ramer et al., 1998; Zanjani et al., 2006), has effects on sleep and wakefulness behavior (Morrow and Opp, 2005) and learning and memory (Balschun, 2004; Heyser et al., 1997).

IL-6 and its role in the immune system

The immune system is essential for survival; recognizes and eliminates viruses, bacteria and other pathogens. In this context, the first discovered function of IL-6 was to differentiate B cells into antibody-secreting cells (Muraguchi et al., 1981). In 1994 it was shown that IL-6 deficient mice, although develop normally, show an altered response to infections , with severe defects in T-cell regulated antibody production and abolition of the orchestrated acute phase response in the liver after infection and trauma (Kopf et al., 1994).

The signaling pathway of the IL-6 helps promote and coordinate pro-inflammatory activities of cells throughout the body , and contributes to increased survival and proliferation of immune cells, the production of antibodies by B lymphocytes, and to the change of metabolic function by altering the use of lipids and glucose. Through these and other functions, IL-6 also helps promote chronic inflammation by stimulating and facilitating interactions between the innate and adaptive immune systems. At sites of infection or injury, first the neutrophils and other infiltrating cells of the innate immune system release IL6, as do adjacent endothelial cells, which stimulates these cell types to carry out their respective functions.

High concentration effect IL6

The IL-6 at permanently elevated levels can play a key role in altering homeostasis in different physiological processes , which can contribute to the appearance of the pathological processes observed in diseaseschronic inflammatory and autoimmune such as rheumatoid arthritis..

Prolonged elevation IL-6 in serum can have far-reaching effects. In addition to inflammatory effects , elevated IL-6 levels can also affect metabolism (lipids, glucose), hematopoiesis, the central nervous system, and the immune response.

In rheumatoid arthritis, elevated levels of IL-6 have been associated to disease activity joint destruction, and systemic manifestations, and may contribute to fatigue, anemia, osteoporosis, and cardiovascular disease .

Low concentration effect of IL-6

A decrease in IL-6 levels is associated with poor defense against various pathogens.

Functions of the IL-6

In the inmune system:

It acts as a B cell differentiation factor in antibody-producing cells (Muraguchi et al., 1981).

Induces neutrophil differentiation and participates in the transition from the innate immune response to the adaptive immune response(Xing et al., 1998)

It regulates the differentiation of Th17 cells(Bettelli et al., 2006).

It acts as growth factor of myeloma and plasmacytoma cells(Bataille et al., 1989).

In skeletal muscle:

Increases glucose uptake and GLUT4 transporter expression(Carey et al., 2006).

Increases the oxidation of fatty acids (Carey et al., 2006).

Activates lipolysis(Al-Khalili et al., 2006 ).

Increases AMPK levels(Al-Khalili et al., 2006; Carey et al., 2006; Kahnet al., 2005).

In adipose tissue:

Increases lipolysis (Trujillo et al., 2004).

Increases the secretion of fatty acids(van Hall et al., 2003).

Decreases LPL activity (Trujillo et al., 2004).

Increases leptin secretion and reduces adiponectin secretion (Trujilloet al., 2004).

Increases the oxidation of fatty acids (van Hall et al., 2003).

Induces macrophage infiltration in the WAT (Weisberg et al., 2003).

Induces insulin resistance(Lagathu et al., 2003; Rotter et al., 2003).

In the central nervous system:

It participates in neuroinflammation increasing the astrogliosis and microgliosis(Balasingam et al., 1994; Woiciechowsky et al., 2004).

Induces the differentiation of neurons(Cao et al., 2006; Hirota et al., 1996; Zhang et al., 2007).

Participates in astrogliogenesis and neurogenesis(Kang and Kang, 2008; Nakanishi et al., 2007; Vallieres et al., 2002).

It promotes the survival of various neuronal types(Marz et al., 1998; Murphy et al., 2000; Schafer et al., 1999; Thier et al., 1999; Valerio et al.,2002; von Coelln et al., 1995).

Participates in the induction of the fever (Chai et al., 1996; Schobitz et al., 1995).

It is involved in emotional behavior (Armario et al., 1998; Butterweck et al., 2003).

Activate the HPA axis(Girotti et al., 2012).

Participates in the pain (Murphy et al., 1999; Ramer et al., 1998).

Participates in the regulation of the sleep cycle and wake (Morrow and Opp, 2005).

Participates in learning and memory (Balschun et al., 2004; Heyser et al.,1997).

Participates in the control of energy homeostasis (Hidalgo et al., 2010; Li et al., 2002; Wallenius et al., 2002a).

In the pancreas:

It promotes the proliferation of α cells (Ellingsgaard et al., 2008).

Regulates the expression and secretion glucagon (Ellingsgaard et al., 2008).

In the liver:

It promotes liver regeneration (Cressman et al., 1996).

Induces acute phase protein synthesis (Fattori et al., 1994; Xing et al.,1998).

Increases the production of the hepatic glucose production during exercise (Keller et al. 2001).

Decreases the G6pase expression (Inoue et al., 2006; Franckhauser et al.,2008).

Inhibits glycogen synthesis (Senn et al., 2002).

Increases the triglyceride secretion (Fasshauer and Paschke, 2003; Hong et al.,2004).

Inhibits insulin signaling and increases the risk of developing insulin resistance (Senn et al., 2002)

Associated pathologies

Anemia (via hepcidin production)
Cardiovascular disease
Deregulation of lipid metabolism
Diabetes
Polymorphism
Arterial hypertension
Obesity
Dysregulation of the hypothalamic-pituitary axis (fatigue, depression and sleep disorders)
Arthritis
Multiple sclerosis
Osteoporosis
Crohn´s disease

IL-6 in rheumatoid arthritis

Rheumatoid arthritis (RA) is a autoimmune disease, progressive and chronic that is characterized by presenting joint and systemic manifestations debilitating . Joint manifestations include pain, hypersensitive and swollen joints and morning stiffness. Although the course of the disease varies between patients, RA leads to progressive destruction of the joints and functional loss in most cases, which can lead to a physical disability.

Systemic manifestations may include anemia, fatigue, osteoporosis, cardiovascular disease (CVD), rheumatoides nodules, and vasculitis. These manifestations can negatively influence the prognosis and survival of patients with RA.

Have been shown that RA and other inflammatory diseases are consequence of the activity of a complex network of cytokines, including the tumor necrosis factor, the interleukins, and interferons. IL-6 is a multifunctional cytokine that performs numerous and diverse functions, including vital proinflammatory functions in response to infection or injury.

Beneficial ingredients:

The future of nuttrition plays a very important role in combating diseases caused by interleukin 6.

For this we must make a change in our diet, which will be of great help and in turn will complement the therapy of the effects caused by IL-6.

Introdution of ingredients that help to reduce inflamation in the affected area is very important to be able to regulate this essential cytokine for our health.

One of the most relevant ingredients is the eggshell membrane, that is why we have developed Eggsell Membrane ESM that favors the reduction of inflammation of interleukin 6 according to the UCAM study.

Our product ESM is an ingredient 100% natural made from the internal membrane of the eggshell.

Some of its benefits include:

Improved joint flexibility
Decreased joint stiffness
Decreased joint pain
Strengthening of the joints
Nourishes articular cartilage
Improving quality of life
100% natural product with no side effects
Natural source of chondroitin sulfate, hyaluronic acid, and other glycosaminoglycans with key proteins like essential collagen for healthy joints. Small daily dose of 500 mg
Positive effects from the first month of treatment
Non-chemical and environmentally friendly manufacturing process

It should also be borne in mind that ESM is the ideal ingredient for nutritional applications both in food and in food supplements and nutritional supplements.

Some of its applications are:

Prevent and combat the signs of joint aging
Inflammatory processes of the joints
Osteoarticular degenerative processes
Connective tissue regenerator

Conclusión:

Interleukin 6 is a cytokine with many biological functions. Some are proinflammatory while others are anti-inflammatory.

It is involved in the pathophysiology of different autoimmune diseases and in other conditions such as atherosclerosis and osteoporosis.

Has been largely deciphered mechanisms of action and signal transductions, which has facilitated the development of drugs with the ability to inhibit their functions. Recent clinical studies have shown that blocking the actions of this cytokine can be very beneficial, particularly in patients suffering from RA as well as in other diseases, it has been shown that interleukin 6 can play a very important role.

Although the network of pathways that regulate energetic homeostasis is not fully understood, what is known to date, allows us to appreciate the diversity of functions in which the adipose cell directed by IL-6 participates.