Interleukins

Interleukins (from Latin/Greek inter = between; leukos = white; kinein = to move) are a group of endogenous, short-chain regulatory proteins (cytokines) of the immune system (IL1-IL35). Interleukins are mediators for induction, course and control of T-cell-mediated cytotoxic immune reactions as well as B-cell activation (antibody production). They are mainly formed and secreted by stimulated leukocytes, monocytes and macrophages. So far, about 35 different interleukins have been clearly identified. Each cytokine of the interleukin group is nomenclatically assigned a number for its classification (IL-1 to IL-35).

Some functionally related cytokines are grouped into cytokine (or interleukin) families. One example is the IL-2 family. In addition to interleukin-2 as a T-cell growth factor, interleukin-15, which can partially replace interleukin-2 in this function, belongs to this family. Furthermore interleukin-21, which induces cell division and proliferation of NK cells and cytotoxic T lymphocytes.

Another example is the Interleukin-10 family. To this cytokine family belong: Interleukin -10 and the homologous interleukin -19 and -20; furthermore the interleukins -22,-24, -26.

Interleukin-1 (IL-1; lymphocyte-activating factor [LAF]): First described in the 1940s as a so-called "endogenous pyrogen". It is formed and secreted by macrophages.

Interleukin-2 (IL-2) is therapeutically one of the most important interleukins. It is secreted during immune reactions of malignant tumours and causes the production of T-helper cells.

Interleukin-3 (IL-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) acts (like IL-10 and IL-11) as a so-called anti-inflammatory cytokine by preventing excessive inflammatory reactions and is therefore important for the homeostasis of the immune system. Furthermore, IL-4 stimulates B-cell activation and IgE production.

Interleukin-5 (IL-5 or T-cell-replacing factor): Product of activated T-helper cells. Effect on activated B-cells and increase in antibody production. Il-5 has a positive chemotactic effect on eosinophil granulocytes and increases the synthesis and secretion of immunoglobulin A by plasma cells.

Interleukin-6 (IL-6) - glycoprotein with a molecular weight of 21 kD. IL-6 is produced by activated T cells, macrophages, fibroblasts and endothelial cells.

Interleukin-7 (IL-7) is produced by stromal cells of the lymphatic organs and stimulates the growth of precursor cells of B and T lymphocytes.

Interleukin-8 (IL-8) is a chemokine of the CXC family and is produced by endothelial cells, monocytes, epithelial cells and fibroblasts, among others. An important target of the chemokine are neutrophil granulocytes.

interleukin-9

Interleukin-10 (IL-10) acts (like IL-4 and IL-11) as a so-called anti-inflammatory cytokine by inhibiting macrophage function and thus preventing excessive inflammatory reactions. It is mainly produced by TH2 cells and regulatory T cells.

Interleukin-11 (IL-11) acts (like IL-4 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 influences the course of intracellular infections.

Interleukin-13 is produced by T lymphocytes and stimulates the formation and differentiation of B lymphocytes. Furthermore IL-13 inhibits the activation of macrophages.

interleukin-14

interleukin-15

Interleukin-16 (IL-16) is elevated in acute and chronic atopic eczema. It also appears to play a role in rheumatoid arthritis.

Interleukin-17 (IL-17) is predominantly expressed by CD4 lymphocytes and eosinophilic leukocytes. Furthermore, neutrophil granulocytes, mast cells, gamma/delta T cells, natural killer (NK) cells and innate lymphoid cells also produce relevant amounts of IL-17A. IL-17 stimulates, among other things, the production of IL-6 and IL-8. IL-17 plays a central role in the pathogenesis of psoriatic inflammation. Antibodies against IL-17A are successfully used in psoriasis therapy.

Interleukin-18 (IL-18) has been detected in elevated concentrations in the synovia of patients with rheumatoid arthritis.

interleukin-19

interleukin-20

interleukin-21

interleukin-22

interleukin-23

interleukin-24

interleukin-25

interleukin-26

interleukin-27

interleukin-28

interleukin-29

interleukin-30

interleukin-31

interleukin-32

interleukin-33

interleukin-34

interleukin-35

In the meantime, a whole series of recombinant antibodies against various drugs exist. Interleukins themselves or against their receptors (Interleukin-R). These are used in the immunotherapy of various diseases:

• Interleukin-1.R antagonist: Anakinra (rheumatoid arthritis)
• Interleukin-2-R antibody: Basiliximab, Daclizzumab (prophylaxis of transplant rejection)
• Interleukin-6-R antibody: Tocilizumab (rheumatoid arthritis)
• Interleukin-1beta antibody: Canakinumab (Hereditary fever syndromes)
• Interleukin-5 antibody: Mepolizumab (Churg-Strauss syndrome)
• Interleukin-12/23 antibody: Ustekinumab (severe psoriasis)

Influence on the CYP450 metabolism

In addition to the desired effects, the side effects of the interleukins and their antibodies are of great importance for therapeutic use (see below the individual cytokines). For example, interleukin-6 and interleukin-1 suppress the formation of the hepatic cytochrome P450 enzymes (CYP450). If patients take drugs with a narrow therapeutic range that are metabolised by cytochrome P450 enzymes, e.g., ciclosporin, calcium channel blockers, theophylline, warfarin, phenytoin or benzodiazepines, their therapeutic blood levels should be monitored and, if necessary, adjusted.

At the beginning of interleukin research, each newly discovered cytokine was named after its in vitro effect. However, after isolating the proteins and identifying their DNA sequence, it quickly became clear that only a limited number of compounds exist that act simultaneously on several cell types and cause different effects there. These are therefore pleiotropic proteins with numerous and also different cell functions.

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2. Fernándes-Rivas et al (2004) Anaphylaxis to raw carrot not linked to pollen allergy. Allergy 59: 1239-1240
3. Morena-Ancillo et al (2006) Role of Dau c 1 in three different patterns of carrot-induced asthma. Allergol Immunopathol 34: 116-120
4. Simon D et al (2007) Anti-interleukin-5 therapy for eosinophilic diseases. dermatologist 58: 122-127