Interleukins (IL-x) are the cytokines counting peptide hormones , d. In other words , they are the body's own messenger substances in the cells of the immune system . The word interleukin comes from the Latin: inter = between and Greek leukos = white .
Interleukins mediate communication between leukocytes , but also other cells involved in the immune reaction (e.g. macrophages ). They are formed by CD4- positive T helper cells , monocytes , macrophages and endothelial cells and act on cells of the blood-forming system . According to the order in which they were discovered, they are divided into several subgroups, which are identified by numbers.
The effect of the interleukins is very different. While interleukin-2 is released by the T cell and has a positive effect on the growth of this cell, interleukin-10 inhibits the activity of the macrophages and curbs the defense reaction. Interleukins specifically stimulate certain cells of the immune system to grow, mature and divide or prevent precisely these processes of activation.
Interleukin-1 (IL-1) is produced by macrophages , endothelial cells , fibroblasts and a few other cells and is a signaling substance that promotes inflammation. Endothelial cells react to it by incorporating special receptors (e.g. E-selectin) into the cell membrane. A leukocyte in the blood now binds to this receptor and can migrate into the damaged tissue. In doing so, it displaces endothelial cells and cuts its way through the basal lamina .
The displacement and destruction of cells and connective tissue is necessary to combat pathogens and defective or degenerate cells outside the bloodstream. However, with chronic inflammation, this reaction can get out of control. IL-1 accumulates on the chondrocytes and causes the release of cartilage-destroying enzymes , which leads to the breakdown of cartilage substance and ultimately to the destruction of the joints. In the field of orthopedics , therapy with an IL-1 antagonist has been practiced since about 1998 , which is obtained from the body's own blood and injected in an enriched form into a diseased joint . The studies carried out so far suggest a therapy option for early forms of osteoarthritis . As an inhibitor for example is diacerein used.
In schizophrenic patients, altered IL-1 values were found in the blood, in the cerebral fluid and in the (prefrontal) cortex in the frontal lobe area.
Interleukin-1α is produced in many cell types but is mainly only secreted by monocytes and macrophages . This cytokine plays an important role in maintaining the skin barrier function and in various immune reactions. Due to its ability to control the production of dermis components such as B. to stimulate collagen , it is used in the cosmetics industry.
- see main article Interleukin-1β
Interleukin1β (IL-1β) is mainly produced by blood monocytes and is a central messenger substance in the response of the host organism to a number of external influences (such as lipopolysaccharides as exogenous pyrogens ). It is described in more detail in the corresponding sub-article.
- see main article Interleukin-2
Interleukin-2 (IL-2) is the most important signal for a T helper cell . After recognizing its antigen on the MHC-II receptor of an antigen-presenting cell, the T helper cell releases IL-2. This signal has an autocrine effect on itself. An intracellular signal cascade activates and clonal division of the T cells. Once they have recognized their antigen, they multiply, which is why this interleukin is one of the growth factors . In addition to the autocrine T-cell activation, IL-2 also acts on B lymphocytes and natural killer cells (NK cells) with the same effect. The production of T H 2 cytokines IL-4 and IL-5 requires IL-2.
IL-2 is one of the most important interleukins therapeutically.
Interleukin-3 (also: Multipotential CSF )
Interleukin-3 acts on the stem cells in the bone marrow and is used to stimulate blood formation after chemotherapy , bone marrow or stem cell transplantation .
Interleukin-4 (IL-4) (formerly B cell growth factor (BCGF) or B cell stimulating factor (BSF)) is a cytokine with anti-inflammatory properties, which among other things, the body's own production of Th1 cells and macrophages and IFN -gamma and IL-12 decreased. It is therefore important for the homeostasis of the immune system. IL-4 differentiates naive CD4 + T cells (Th0) into Th2 cells, which are generally assigned an anti-inflammatory role. IL-4 ensures stimulation and proliferation of activated B and T cells and leads to an immunoglobulin class switch to IgE and IgG4. Furthermore, IL-4 has the potential to upregulate the expression of MHCII molecules on B lymphocytes. In addition, IL-4 plays an important role in the adhesion to endothelial cells and the subsequent chemotaxis by leukocytes.
The main source of IL-4 are Th2 cells themselves. Other sources are basophils and eosinophils, mast cells and NK cells.
IL-4 can be bound by two different receptors on various cells (muscle tissue, liver cells, brain tissue, connective tissue, hematopoietic, endothelial, epithelial cells).
Interleukin-5 has a positive chemotactic effect on eosinophilic granulocytes and increases the synthesis and secretion of immunoglobulin A by plasma cells . It is produced by type 2 T helper cells and mast cells.
- see main article Interleukin-6
Interleukin-6 (IL-6) causes the increased synthesis of acute phase proteins in the liver . Both pro- and anti-inflammatory effects are discussed. IL-6 is released ( secreted ) mainly by monocytes / macrophages, but also by epithelial and endothelial cells . It is important for the prognosis and assessment of trauma and sepsis .
Interleukin-7 is produced by stromal cells of the lymphatic organs and stimulates the growth of precursor cells of B and T lymphocytes.
- see main article Interleukin-8
Interleukin-8 (IL-8) is a chemokine of the CXC family and is produced by endothelial cells, monocytes, epithelial cells and fibroblasts , among others . Neutrophils are an important target of the chemokine . The main biological effects of IL-8 on granulocytes include the promotion of chemotaxis, the stimulation of the expression of adhesion molecules and the activation with the release of oxygen radicals and granules, which are mediated via the chemokine receptors CXCR1 and CXCR2 .
Interleukin-9 (IL-9) is a cytokine that is produced by special white blood cells. It is a subgroup of CD 4+ T cells, the so-called Th9 cells (h stands for helper). IL-9 has many functions in lymphoid cells and mast cell lines. It's associated with allergic inflammation. It is believed that this cytokine plays a role in the development of asthma and ulcerative colitis. In the lungs of asthmatics , IL-9 and the IL-9 receptor are more strongly expressed than in healthy lungs.
- see main article Interleukin-10
Interleukin-10 (IL-10) acts (like IL-4 and IL-11) as a so-called anti-inflammatory cytokine by inhibiting the macrophage function and thus preventing excessive inflammatory reactions. It is mainly produced by T H 2 cells and regulatory T cells.
Interleukin-11 acts (like TGF-β and IL-10) as a so-called anti-inflammatory cytokine by preventing excessive inflammatory reactions and is therefore important for the homeostasis of the immune system.
Interleukin-12 (IL-12) has a central function in the initiation and continuation of a T helper cell-1 (TH-1) immune response (cellular defense) and has an influence on the course of intracellular infections . Recent research results suggest that IL-12 can also activate enzymes, which are then able to quickly repair damaged genetic material. Another proven effect of IL-12 is that it increases the ability of killer T cells to invade and destroy a tumor . IL-12 is a heterodimeric cytokine that is mainly produced by monocytes / macrophages. The production of IL-12 can be implicated in the pathogenesis of autoimmunity.
Some microorganisms, such as Candida albicans , have IL-12 inhibiting factors.
Interleukin-13 (IL-13) is produced by T lymphocytes and stimulates the formation and differentiation of B lymphocytes. Furthermore, IL-13 inhibits the activation of macrophages.
Interleukin-16 (IL-16) is initially formed as a pro-peptide (80 kDa) and only then is cleaved into a 14 kDa monomer by caspase-3. The structure of the biologically active form of IL-16 corresponds to a homotetramer. IL-16, the gene of which is located on chromosome 15 , is mainly produced by CD8 + T cells. In addition, various other cell types including mononuclear phagocytes, mast cells, eosinophil granulocytes, and CD4 + T cells can produce this cytokine. For its biological effect, IL-16 binds to the glycoprotein CD4, which thereby assumes the additional function of a cytokine receptor. IL-16 was identified early on as a CD4 + cell-specific chemotaxin. In addition, this cytokine causes the transition from a G 0 to a G 1 phase of the cell cycle in native T cells and at the same time promotes the surface expression of the complete IL-2 receptor. This stimulates these cells to proliferate as a result of exposure to IL-2 and IL-16 . The interaction of IL-16 with its cellular receptor CD4 can lead to an antigen-independent cell proliferation. This fact is of special significance in HIV-infected patients, since there the serum concentration of IL-16 is associated with the severity of the infection. IL-16 also plays a role in Crohn's disease , multiple sclerosis , and autoimmune thyroiditis .
Interleukin-17 (IL-17) is the signal cytokine of the newly described Th17 cell type, which is associated with various autoimmune diseases in mouse models . Other cytokines of this cell type are IL-21 and IL-22. IL-17 appears to be involved in mediating the inflammatory process in fibroblasts. He is also assigned a role in neutrophil recruitment. A main producer of IL-17 are the TH17 cells named after him .
IL-17 plays an important role in the development of arterial hypertension . Interleukin-17 has a proinflammatory effect in the smooth muscle cells of the vessels and promotes the release of the mediators interleukin 6 , CXCL-8 and CXCL-10 as well as CRP . In animal studies, both anti-IL-17 therapy and a gene deletion of IL-17 have lowered blood pressure. In addition, a subgroup of patients with severe asthma also has elevated IL-17 levels.
Interleukin-18 (IL-18) is a cytokine that belongs to the IL-1 cytokine superfamily, has functional similarities to IL-12 and has an important role as a regulator of natural and adaptive immunity . Formed from a 24-kDa precursor peptide, IL-18 (analogous to IL-1β) is split into its bioactive 18-kDa form by the Interleukin-1 Converting Enzyme Protease (also called Caspase-1 ). IL-18 is produced by a variety of hematopoietic and non-hematopoietic cells, including macrophages , dendritic cells , Kupffer cells , keratinocytes , osteoblasts , intestinal epithelial cells , microglia , fibroblasts and cells of the adrenal cortex . The receptor complex specific for the cytokine, IL-18R, corresponds to a heterodimer consisting of a ligand-binding α-chain and a signal-transducing β-chain. The IL-18R is mainly expressed on macrophages, neutrophils, NK cells and endothelial cells of the smooth muscles.
Increased concentrations of IL-18 were found in the synovial membrane of patients with rheumatoid arthritis .
- see main article Interleukin-21
Interleukin-21 is a cytokine with important regulatory effects on cells of the immune system, including NK cells and cytotoxic T cells, which can destroy cancer cells or infected with a virus. It also plays a role in Hodgkin's lymphoma .
Psoriasis ( psoriasis sufferer) patients form reinforces the messenger interleukin-22nd The more of it there is in the skin, the more pronounced the disease. Tests on mice show that the IL-22 blockade dampens inflammation and reduces pathological skin growth. In contrast, IL22 injections trigger psoriasis-like symptoms in healthy animals.
In many autoimmune diseases such as rheumatoid arthritis , multiple sclerosis , psoriasis and Crohn's disease , interleukin-23 can stimulate the formation of T cells, which then turn against the body. It can also hinder the indirect tumor-destroying effects of IL-12.
Interleukin-31 is produced by lymphocytes , especially by activated CD4- positive T cells . IL-31 receptors are heterodimers made up of the interleukin-31 receptor A and the oncostatin M receptor β-subunit OSMRβ. The IL-31 receptor A is most strongly expressed in the sensory nerve cells of the spinal ganglia of the spinal cord , which also have increased co-expression of pruritus sensors and inflammatory mediators of neurogenic inflammation, which include TRPV-1 and NPPB . Interleukin 31 also induces phosphorylation and thus activation of the signal transducers of the JAK-STAT signaling pathway JAK1 and JAK2, which are known as mediators of pruritus . Hence, IL-31 has been named the "pruritus cytokine".
IL-31 could be a potential pharmacological target of therapy for itching, e.g. B. in the form of an antagonist in many diseases associated with itching ( pruritus ) ( atopy , cholestasis , uremia ). It is controversial whether histamine plays a role in causing itching.
In veterinary medicine, Lokivetmab is a monoclonal antibody against IL-31 that blocks the effect of this interleukin and thus greatly reduces itching in atopic dermatitis .
In 2020, a phase II study with nemolizumab was published in human medicine . This humanized antibody against the human interleukin-31 receptor significantly reduced the itch score in prurigo nodularis , a particularly severe form of chronic itch.
The cytokine interleukin-33 is released when the lungs are first expanded immediately after birth - investigated in mice and humans in 2017. IL-33 activates immune cells in the lung tissue.
Use as a therapeutic agent
In immunotherapy or immunomodulation with interleukin, for example with IL-2 in cancer immunotherapy against metastatic renal cell carcinoma , an attempt is made to stimulate the immune defense of an organism . Malignant tumors or an infection , for example due to HIV , should be countered by administering them with the body's own agents.
In the treatment of malignant tumors (renal cell carcinoma, malignant melanoma ), combination preparations of interleukin and other agents, such as interferon and / or cytostatics, are mostly used . The side effects of therapy with IL-2 are considerable: for example fever, tiredness, skin rashes, palpitations, edema or vascular leak syndrome . However, these side effects are largely reversible.
Today so-called "anti-interleukins" are often and successfully used in Crohn's disease and especially in autoimmune rheumatic diseases .
- Cytokines & Cells Online Pathfinder Encyclopedia Page for the scientifically interested with short reviews of many cytokines (English)
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- ↑ MR Duncan, B. Berman: Differential regulation of collagen, glycosaminoglycan, fibronectin, and collagenase activity production in cultured human adult dermal fibroblasts by interleukin 1-alpha and beta and tumor necrosis factor-alpha and beta . In: Journal of Investigative Dermatology . tape 92 , no. 5 , May 1989, pp. 699-706 , PMID 2541208 .
- ↑ Florian Horn, Gerd Lindenmeier, Isabelle Moc, Christian Grillhösl, Silke Berghold, Nadine Schneider, Birgit Münster Horn: Human biochemistry: The textbook for medical studies . 3. Edition. Thieme, Stuttgart 2005, ISBN 978-3-13-130883-2 , p. 411 .
- ↑ W. Holter, O. Majdic, FS Kalthoff, W. Knapp: Regulation of interleukin-4 production in human mononuclear cells . In: European Journal of Immunology . tape 22 , no. 10 , October 1992, p. 2765-2767 , PMID 1356786 .
- ^ A b Clare M Lloyd, James A Harker: Epigenetic Control of Interleukin-9 in Asthma. The New England Journal of Medicine 2018; Vol. 379, Issue 1: 87-89. DOI: 10.1056 / NEJMcibr1803610
- ↑ Mark H. Kaplan, Ritobrata Goswami: A Brief History of IL-9 . In: The Journal of Immunology . tape 186 , no. 6 , March 15, 2011, ISSN 1550-6606 , p. 3283-3288 , doi : 10.4049 / jimmunol.1003049 , PMID 21368237 , PMC 3074408 (free full text) - ( jimmunol.org [accessed December 21, 2018]).
- ↑ K. Gerlach, Y. Hwang u. a .: TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. In: Nature Immunology . Volume 15, Number 7, July 2014, ISSN 1529-2916 , pp. 676-686, doi: 10.1038 / ni.2920 , PMID 24908389 .
- ↑ BM Segal, DM Klinman, EM Shevach : Microbial products induce autoimmune disease by an IL-12-dependent pathway . In: Journal of Immunology . tape 158 , no. June 11 , 1997, p. 5087-5090 , PMID 9164922 .
- ↑ N. Tang, L. Liu et al. a .: Inhibition of monocytic interleukin-12 production by Candida albicans via selective activation of ERK mitogen-activated protein kinase. In: Infection and Immunity . Volume 72, Number 5, May 2004, ISSN 0019-9567 , pp. 2513-2520, PMID 15102758 , PMC 387890 (free full text).
- ↑ Sandra C. Christiansen, Bruce L. Zuraw: Treatment of Hypertension in Patients with Asthma New England Journal of Medicine 2019, Volume 381, Issue 11 of September 12, 2019, pages 1046-1057, DOI: 10.1056 / NEJMra1800345
- ↑ Claude Kaufmann: Multiple sclerosis: attack on one's own nerve cells. University of Zurich, May 19, 2005, accessed May 15, 2008 .
- ↑ Antibody works against psoriasis. science.ORF.at, March 9, 2015, accessed on August 18, 2019 .
- ↑ Tamara Kopp et al .: Clinical improvement in psoriasis with specific targeting of interleukin-23. In: Nature 521, pages 222-226, May 14, 2015 doi: 10.1038 / nature14175
- ↑ Shawn G. Kwatra: Breaking the Itch – Scratch Cycle in Prurigo Nodularis , New England Journal of Medicine 2020, Volume 382, Issue 8 February 20, 2020, pages 757-758, DOI: 10.1056 / NEJMe1916733
- ↑ Akiko Takaoka, Iwao Arai, Masanori Sugimoto, Akie Yamaguchi, Makoto Tanaka, Shiro Nakaike: Expression of IL-31 gene transcripts in NC / Nga mice with atopic dermatitis . In: European Journal of Pharmacology . tape 516 , no. 2 , June 2005, p. 180-181 , doi : 10.1016 / j.ejphar.2005.04.040 .
- ↑ Hilde Moyaert et al .: A blinded, randomized clinical trial evaluationg the efficacy and safety of lokivetmab compared to ciclosporin in client owned dogs with atopic dermatitis. In: Vet. Dermatology , September 2017 doi : 10.1111 / vde.12478
- ↑ Sonja Ständer, Gil Yosipovitch, Franz J. Legat, Jean-Philippe Lacour, Carle Paul, Joanna Narbutt, Thomas Bieber, Laurent Misery, Andreas Wollenberg, Adam Reich, Faiz Ahmad, Christophe Piketty: Trial of Nemolizumab in Moderate-to-Severe Prurigo Nodularis , New England Journal of Medicine 2020, Volume 382, Issue 8 February 20, 2020, Pages 706-716, DOI: 10.1056 / NEJMoa1908316
- ↑ Silvia Knapp, MedUni Vienna. In: The first breath and the immune system . Dimensions - the world of science, Ö1, ORF-Radio, broadcast March 3, 2017. 10: 05–19: 30. Here: 19:09. Available for 7 days.
- ↑ Cytokines in cancer therapy. In: krebsinformationsdienst.de. September 1, 2014, accessed June 1, 2015 .