Interleukin-6 – Wikipedia

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Interleukin-6 (short: Il-6 , Synonyms older names: Interferon-β2 ( IFNB2 ), B cell stimulating factor , B cell differentiation factor , Liver cell stimulating factor ) belongs to the interleukins (or more comprehensive to the cytokines), which regulate the inflammatory reaction of the organism. IL-6 comes through the type of its complex regulation and functions in the orchestra of the other cytokines and cells. a key position in the transition of mechanisms of innate immunity towards mechanisms of acquired immunity within the inflammatory process. [first] IL-6 belongs to a cytokin family that shares the glycoprotein GP130 receptor subunit. [2] The multifunctionality of cytokines is often incorrectly referred to as pleiiotropy (pharmacology); In this context, however, this name should never be used.

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IL-6 is encoded in humans on chromosome 7 Genocus P21. The gene section contains 5 exons. An inactive pre-course protein is transcribed, which consists of 212 amino acids. The transcription is u. induced via the transcription factors NF-κB, NF-AT, HSF1 and HSF2.

The 184 amino acids are split off for long active interleukin-6 from the precursor protein. Post -translationally, various isoforms (by splitting up peptides, glycosylation, phosphorylation) are generated, the biological meaning of which has not yet been clarified. [3]

The circulating IL-6 is excreted by the liver and kidneys, the half-life in the serum is in the minute range.

The formation of interleukin-6 is reinforced by prostaglandin-E2.

Interleukin-6 can bind two form types as an activating ligand:

  1. to a membrane-bound IL-6 receptor (IL-6R), which only occurs on liver cells and leukocytes and passes on its signals using the receptor-associated, signal transducing glycoprotein GP130
  2. to a soluble IL-6 receptor (Sil-6R). The resulting IL-6/SIL-6R complex binds to the glycoprotein GP130 that occurs in cell membranes of many cell types. This second process is called “IL-6- trans -Signaling ”. It is important for the numerous cells that express GP130 (which occurs ubiquitous), but not IL-6R on their cell surface. IL-6- trans -Signaling is inhibited by naturally soluble SGP130, which inactivates the IL-6/SIL 6R complex, but not IL-6 alone and its effect on the membrane-bound IL-6 receptor.

These two effects provide many starting points for a differentiated regulation of the IL-6 effect:

  1. Regulation of the IL-6 itself;
  2. Regulation of the SIL-6R: In the serum healthy, sil-6r occurs with a concentration of 25–35 ng/ml and this mirror increases significantly in various diseases such as among other things. Rheumatism, AIDS or certain forms of leukemia. Sil-6r can in principle be created either by splitting up the extracellular part of the (on leukocytes and liver cells) membrane IL-6R or through special splicing in the intracellular formation of the IL-6R. The former is z. B. triggered by C-reactive protein or by certain bacterial oxins. Second is z. B. stimulated by oncostatin-M. [4]
  3. Regulation of the soluble glycoprotein GP130.

When activating the glycoprotein GP130 with an IL-6/SIL 6R complex or when activating an IL-6R (on the GP130) by IL-6, a Janus-activated kinase on its domain inside the cell is on a tyrosine Phosphorylated, which activates the JAK-Stat signal path and the Map-Kinase-Weg, which then leads to the transcription of certain target genes in the cell nucleus. [2] [3]

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Traditionally, interleukin-6 is seen as an activator of the acute-phase proteins and as a lymphocyte-stimulating factor.

Inflammatory reaction [ Edit | Edit the source text ]

In the event of an acute inflammatory episode, neutrophil granulocytes are first recruited, which infiltrate the inflammatory stove, then do their work there, die quite quickly and then be replaced by a longer -lasting population of more specific inflammatory cells such as lymphocytes and mononuclear cells. The interleukin-6 effectiveness plays an important role here: With the degree of infiltration through neutrophil granulocytes, the local concentration of Sil-6r increases, which the IL-6- trans -Signaling triggers in the surrounding tissue. This, in turn, leads to a limitation of the accumulation of neutrophil granulocytes in the inflamed tissue. At the same time, the IL-6- trans -signaling CD3 + -T lymphocytes attracted, [first] Which marks the transition of the innate immune response to a learned immune response. Furthermore, IL-6 is involved in the regulation of the apoptosis of leukocytes, with proapoptotic and antapoptotic active components (of which has so far not been known how they are balanced). IL-6 has an antipoptotic effect on resting and activated T-lymphocytes, and it also regulates its differentiation, proliferation, polarization and the immunoglobulin g secretion of B-lymphocytes. Especially with activated T-lymphocytes, the soluble SIL-6R is necessary to impart these effects because activated T-lymphocytes usually have no membrane IL-6 receptors. Monocytes are differentiated into macrophages by IL-6. [first]

Effect on hormone secretion [ Edit | Edit the source text ]

IL-6 increases (in descending order) the secretion of cortisone, somatotropin, glucagon and adrenaline. [3]

Interleukin-6 is released by strong muscle stress-especially over a longer period of time (6 hours). The maximum of the distribution can be found at the end of the muscle stress. After that, the IL-6 concentration quickly drops again. The IL-6 comes from the stressed muscle cells itself. After long training, the body adapts to it and releases less interleukin-6 when the stress and during the stress breaks. [3]

The concentration of IL-6 in plasma is approx. 1 pg/ml (or 0.001 ng/ml) in healthy people and can increase up to 1000 pg/ml (or 1 ng/ml) for severe systemic infections. Less dramatic climbs can be found in a number of inflammatory and infectious diseases as well as (depending on the dose) during muscle effort. Overall, IL-6 reacts very quickly, its half-life in the serum is in the minute range. These characteristics are used in intensive care medicine to rap in the rapid assessment of acute septic clinical pictures.

A pathogenetic role of IL-6 is discussed in the metabolic syndrome, since a chronically slightly increased serum il-6 (10 pg/ml) can occur. [3]

A connection between increased interleukin-6 serum mirror and the frequency of cardiovascular events was found. In a multicenter cohort study with 14 611 patients with chronic coronary syndrome, more events (heart attack, stroke or cardiovascular death) occurred significantly in the course of the interleukin 6 serum level. [5]

Specific antibodies have been developed against the IL-6 receptor to block the IL-6 effectiveness: Tencilizumab, an IL-6 receptor antibody that is used in the treatment of certain forms of rheumatism.

Interleukin-6 may offer a new approach in the therapy of Alzheimer’s disease. Animal experimental studies showed that cytokine can cause the microglia to reduce plaques. [6]

IL-6 was also identified as a possible trigger of the inflammatory reaction in the event of severe osteo gland inflammation and is discussed in combination with other immune markers for early diagnosis of serious courses in the pancreatitis. [7]

  1. ↑ a b c Simon A. Jones: Directing Transition from Innate to Acquired Immunity: Defining a Role for IL-6 . In: The Journal of Immunology . Band 175 , No. 6 , 2005, ISSN  0022-1767 , S. 3463–3468 , doi: 10.4049/Jimmunol.175.6.3463 , PMID 16148087 .
  2. ↑ a b Peter C. Heinrich, Iris Behrmann, Serge Haan, Heike M. Hermanns, Gerhard Müller-Newen, Fred Schaper: Principles of interleukin (IL)-6-type cytokine signalling and its regulation . In: Biochemical Journal . Band 374 , No. first , 2003, S. 1–20 , doi: 10.1042/bj20030407 , PMID 12773095 .
  3. ↑ a b c d It is C. P. Fischer: Interleukin-6 in acute exercise and training: what is the biological relevance? ( Memento from April 13, 2015 in Internet Archive ) (PDF; 613 kB) In: Excer Immunol Rev. Band 12, 2006, S. 6–33; PMID 17201070 .
  4. ↑ S. A. Jones, et al.: C-reactive Protein: A Physiological Activator of Interleukin-6 Receptor Shedding. In: Journal of Experimental Medicine. 189, 1999, S. 599–604 ( jem.org PDF).
  5. ↑ Gorav Batra, Tatevik Ghukasyan Lakic, Johan Lindbäck, Claes Held, Harvey D. White: Interleukin 6 and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Chronic Coronary Syndrome . In: JAMA cardiology . Band 6 , No. twelfth , December 1, 2021, ISSN 2380-6591 , S. 1440–1445 , doi: 10.1001 / Jamaacardio.2021.3079 , PMID 34431970 , PMC 8387946 (Free full text).
  6. ↑ Paramita Chakrabarty, Karen Jansen-West, Amanda Beccard, Carolina Ceballos Diaz, Yona Levites, Christophe Verbeeck, Abba C. Zubair, Dennis Dickson, Todd E. Golde, Pritam Das: Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition . In: FASEB Journal . Band 24 , No. 2 , February 2010, ISSN 1530-6860 , S. 548–559 , doi: 10.1096/fj.09-141754 , PMID 19825975 , PMC 3083918 (Free full text).
  7. ↑ Z. Dambrauskas, N. Giese, A. Gulbinas, T. Giese, P. O. Berberat, J. Pundzius, G. Barauskas, H. Fries: Different profiles of cytokine expression during mild and severe acute pancreatitis. In: World J. Gastroenterol. 16, 2010, S. 1845–1853 PMID 20397261 PMC 285682 (Free full text).
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