Interleukin-6 is one of the most important signaling molecules produced by cells in the immune system. Although interleukin-6 has a multidirectional effect, its main task is to coordinate the inflammatory process in the body, during which its concentration increases up to 100 times.

Contents:

  1. Interleukin-6 - role in the body
  2. Interleukin-6 - activation mechanism
  3. Interleukin-6 - iron metabolism
  4. Interleukin-6 - autoimmune diseases
  5. Interleukin-6 - obesity and other metabolic diseases
  6. Interleukin-6 - mental disorders
  7. Interleukin-6 - determination in the laboratory
  8. Interleukin-6 - determination in the laboratory
  9. Interleukin-6 - targeted therapies

Interleukin-6(abbreviatedIL-6 ) is a signaling molecule belonging to the group of cytokines. IL-6 is produced and secreted mainly by cells of the immune system as:

  • monocytes
  • macrophages
  • lymphocytes

In addition, non-immune cells such as:

  • fibroblasts
  • keratinocytes
  • chondrocytes
  • osteoblasts
  • endothelium

Also some cancer cells can produce IL-6.

Interleukin-6 - role in the body

IL-6 was first identified as a B cell differentiation factor. Later studies have shown that IL-6 has more multi-directional and systemic effects, such as:

  • initiation and development of the inflammatory response
  • inducing protein synthesis, the so-called acute phase
  • stimulation of bone marrow stem cells, especially from the granulocyte and macrophage lineage
  • regulation of bone metabolism by activating osteoclasts
  • activation and differentiation of T cells
  • stimulation of the hypothalamic-pituitary-adrenal (HPA) axis
  • inducing a pyrogenic effect by raising the body temperature and stimulating the production of prostaglandins

Interestingly, it has been shown that IL-6 is a dual-activity cytokine, which means that on the one hand, it can exhibit anti-inflammatory effects by activating the so-called of the classical signaling pathway, it then participates in and inhibits the proliferation of intestinal epithelial cellsprogrammed death (apoptosis). On the other hand, it causes a pro-inflammatory effect by activating the so-called signaling pathway, activating the immune system.

Under physiological conditions, the level of IL-6 in the blood is low. The main factor stimulating the production of IL-6 are bacterial (e.g. LPS) and viral antigens. At the time of infection by microorganisms or tissue damage caused by, for example, trauma, an acute immune response develops and the level of IL-6 rises sharply.

Interleukin-6 - activation mechanism

Microbial antigens are recognized by cellular TLR receptors (Toll-like receptors) found, among others, in on the surface of macrophages. In addition, non-infectious agents such as tissue damage caused by burns can induce cell lysis, which can also be recognized by TLRs. Consequence of TLR activation which induces IL-6 expression in the cell.

The liver has long been considered the primary target organ for IL-6. The liver reacts quickly to the presence of IL-6 through the synthesis of proteins, the so-called acute phase, which include: C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, hepcidin, haptoglobin and alpha-1-antitrypsin. Therefore, in clinical practice, blood levels of acute phase proteins are used to assess the severity of inflammation.

IL-6 then activates a series of immune cells such as T cells and B cells, which then turn into antibody-producing plasma cells. When IL-6 reaches the bone marrow, it stimulates the differentiation of blood stem cells, among others. maturation of megakaryocytes that release platelets. The increase in platelets is characteristic of inflammation.

Using the above-mentioned mechanisms, IL-6 initiates and regulates the acute inflammatory response and facilitates its progression into the persistent phase. Prolonging the persistent phase results in the accumulation of cells of the immune system in the tissues and their destruction. Hence, the production of IL-6 must be strictly regulated, as its incorrect amount may result in the development of inflammatory diseases such as cancer or autoimmune diseases.

Interleukin-6 - iron metabolism

IL-6 induces the production of hepcidin, which influences the regulation of iron levels by influencing the iron transport mechanisms. In this way, hepcidin inhibits iron release from macrophages and hepatocytes, as well as its reabsorption in the intestine.

This mechanism has its biological justification, because during infection, iron deficiency limits the multiplication of microorganisms and is one of the mechanisms of anti-infectious defense.

A consequence of prolonged inflammation andhepcidin excess is anemia associated with chronic diseases.

Interleukin-6 - autoimmune diseases

IL-6 facilitates the development of the acquired immune response and directs its course. Various populations of Th lymphocytes (helper) play an important role in the immune response, which, when activated by appropriate cytokines, can differentiate in a specific direction of the immune response.

IL-6 induces the differentiation of Th lymphocytes into Th17 lymphocytes, which contributes to protection against bacterial or fungal infections. On the other hand, IL-6 inhibits Th1 differentiation, which plays a role in immune homeostasis.

It is believed that the disturbance of regulation in favor of Th17 lymphocytes is involved in the development of autoimmune diseases, as it disturbs the immune tolerance to own tissues. Therefore, while IL-6 may be protective in many infectious diseases, its activity seems to be the key to understanding the pathomechanism of autoimmune diseases.

These observations are confirmed by studies in mice and humans in which blocking the production of IL-6 reduces susceptibility to Castleman's disease, rheumatoid arthritis or systemic lupus erythematosus.

Interleukin-6 - obesity and other metabolic diseases

Currently, it is postulated that obesity is a disease accompanied by low-grade chronic inflammation. Pro-inflammatory macrophages found in pathological adipose tissue are one of the most important sources of IL-6 in people with excess body weight.

Derived from adipose tissue, IL-6 may have an adverse effect on the body's metabolism, among others. through excessive lipolysis and triglyceride release, and a decrease in insulin sensitivity. It has been shown that the concentration of IL-6 in the blood strongly correlates with obesity, insulin resistance and the metabolic syndrome.

Interleukin-6 - mental disorders

People with autoimmune or metabolic diseases very often suffer from chronic fatigue, sleep disorders and excessive daytime sleepiness.

One reason may be activation of the immune-inflammatory pathway initiated by IL-6, which acts as a link between the immune system and the nervous system. Hence, it has the ability to regulate the neurohormonal economy.

Interestingly, the concentration of IL-6 in the body is synchronized with the circadian rhythm, where its concentration is lower during the day and higher at night. This may partly explain the occurrence of somnolence at its non-physiological levels during the day.

The ability of inflammation, especially IL-6, to affect the level of neurotransmittershow serotonin allowed for the speculation that pro-inflammatory cytokines may be associated with mental disorders such as depression or schizophrenia. IL-6 may influence metabolic pathways in the brain through:

  • activation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in increased secretion of the stress hormone - cortisol.
  • reduction of serotonin and melatonin levels as a result of tryptophan shift to the kynurenine pathway (tryptophan is a precursor to the synthesis of serotonin, and then melatonin)
  • neurogenesis, i.e. the process of creating new nerve cells (especially within the hippocampus)

It has been shown that people suffering from depression increase the activity of cells of the immune system and the concentration of IL-6 in their blood.

These observations are also confirmed by studies on laboratory rats which were administered subcutaneously specific mixtures of cytokines.

In rodents, it caused symptoms typical of depression - fatigue, insomnia, lack of appetite. In the scientific literature this is called the "inflammatory theory of depression".

It has been shown that higher levels of IL-6 in childhood (which may result, for example, from traumatic experiences) are associated with an increased risk of developing depression and psychosis in adulthood. Elevated levels of IL-6 are also observed in people with severe schizophrenia and bipolar disorder. Interestingly, its level drops significantly after treatment and in remission.

Interleukin-6 - determination in the laboratory

Studies show that the increase in the concentration of pro-inflammatory cytokines, including IL-6, is 2-4 times higher in the elderly compared to the young. This phenomenon is called "inflammaging," which is the inflammation that accompanies aging.

Although the molecular basis of this phenomenon has not yet been elucidated, it is believed that it may result, among others, from changes in the concentration of sex hormones with age, as the production of IL-6 is dependent on them.

Increased levels of IL-6 in the blood are observed in postmenopausal and andropausal patients. It is believed that the increase in IL-6 levels with age may be one of the causes of aging disorders that resemble symptoms of chronic inflammation, such as osteoporosis, anemia, or an increase in CRP protein.

Interleukin-6 - determination in the laboratory

In inflammatory conditions, the concentration of IL-6 may increase up to 100-fold, therefore its concentration in the blood may be a sensitive but non-specific indicator of inflammation. The concentration of IL-6 is determined from fasting venous blood. The concentration of IL-6 may increase in:

  • in autoimmune diseases, e.g. rheumatoid arthritis,juvenile idiopathic arthritis, inflammatory bowel diseases
  • neoplastic e.g. colorectal cancer, liver cancer, lymphomas
  • neurodegenerative diseases e.g. Alzheimer's disease
  • lung diseases e.g. asthma
  • bacterial and viral infections
  • metabolic diseases e.g. obesity, type 2 diabetes, metabolic syndrome
  • chronic disease anemia
  • mental disorders e.g. depression, schizophrenia
  • osteoporosis
  • thrombosis
  • transplant rejection reactions
  • obstetric complications

Assessment of IL-6 concentration in the blood in clinical practice allows for:

  • assessment of the severity of the infection
  • sepsis diagnosis, especially in newborns
  • assessment of prognosis in acute pancreatitis
  • early risk assessment of transplant rejection
  • monitoring the patient's condition after operations
  • risk pregnancy monitoring

Interleukin-6 - targeted therapies

Given that IL-6-induced inflammation is associated with many chronic diseases, it may be an important therapeutic target. T

ocilizumab is a humanized monoclonal IgG antibody directed against the IL-6 receptor. By binding to the receptor, tocilizumab blocks its signaling through IL-6.

Clinical trials with tocilizumab began in the late 1990s, and it was first officially approved for the treatment of Castleman's disease in Japan in 2005.

Since then, tocilizumab has been adopted as a first-line biological therapy for the treatment of moderate to severe rheumatoid arthritis in over 100 countries and for juvenile idiopathic arthritis in Japan, India, the United States and the European Union.

Clinical trials are currently underway to evaluate the effectiveness of tocilizumab in other chronic diseases.

Another antibody that blocks the IL-6 pathway is sirukumab, which is currently undergoing clinical trials for the treatment of depressive disorders.

About the authorKarolina Karabin, MD, PhD, molecular biologist, laboratory diagnostician, Cambridge Diagnostics PolskaA biologist by profession, specializing in microbiology, and a laboratory diagnostician with over 10 years of experience in laboratory work. A graduate of the College of Molecular Medicine and a member of the Polish Society of Human Genetics. Head of research grants at the Laboratory of Molecular Diagnostics at the Department of Hematology, Oncology and Internal Diseases of the Medical University of Warsaw. Titleshe defended her doctor of medical sciences in the field of medical biology at the 1st Faculty of Medicine of the Medical University of Warsaw. Author of many scientific and popular science works in the field of laboratory diagnostics, molecular biology and nutrition. On a daily basis, as a specialist in the field of laboratory diagnostics, he runs the content department at Cambridge Diagnostics Polska and cooperates with a team of nutritionists at the CD Dietary Clinic. He shares his practical knowledge on diagnostics and diet therapy of diseases with specialists at conferences, training sessions, and in magazines and websites. She is particularly interested in the influence of modern lifestyle on molecular processes in the body.

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Category:

Immune system