Interleukin-17 receptor

Interleukin-17 receptor (IL-17R) is a

Structure of IL-17 receptors is unique in comparison with all other known receptor families. IL-17RA is by far the largest member of the family and has the longest cytoplasmic tail of the family. This cytoplasmic tail provides docking sites for numerous signaling intermediates. However, conformational changes mediated after ligand binding are essential for association of these signaling molecules as well as the second receptor subunit and enable subsequent signal transduction. IL-17RA/RC receptor complex is composed of both alpha helices and beta sheets and its extracellular part contains two fibronectin domains, which are involved in formation of two ligand binding sites.^[8][9]

Intracellular part of IL-17 receptors consists of several structural domains including SEFIR motif, a highly conserved motif within IL-17R family. Although SEFIR motif also serves as signaling molecule in IL-1R or Toll-like receptor families, its signaling features and associated adaptor molecules are quite different in IL-17 receptor family.^[10][11] In case of IL-17RA, it has a longer cytoplasmic tail which contains some additional structural domains, such as TILL domain ("TIR-like loop") or inhibitory CBAD domain ("C/EBPβ-activation domain").^[11][12]

Expression and regulation

IL-17RA has been observed at high levels in various tissues such as haematopoietic, bone marrow, thymus, and spleen tissue. IL-17RA is also normally found at low levels in colon, small intestine, and lung tissues.^[13] IL-17RA is expressed in CD8+ T cells, and upregulated by IL-15 and IL-21. IL-17RA may be internalised after binding IL-17A.^[13]

IL-17RB is highly expressed in the kidney, liver and Th2 cells and its overexpression promotes triggering of Th2 immune response.^[14][15]

IL-17RC expression is low in haematopoietic tissues and high in non-immune cells of the prostate, liver, kidney, thyroid and joints.^[13]

Another family subunit IL-17RE is highly expressed in Th17 cells.^[16]

Function

Signaling via IL-17R protects our body against several bacterial and

Apart from production of these inflammatory products de novo, signaling via IL-17R also promotes stabilization of already existent specific mRNA transcripts. This stabilization prolongs the half-life of mRNAs and prevents their quick degradation. Again, these mRNA transcripts predominantly encode proinflammatory cytokines or chemokines.[22]

Pathology

Although IL-17R provides crucial protection against a variety of microbial infections in humans, it must be very strictly regulated. Immoderate and undue activation of IL-17R by IL-17A results in development of several autoimmune diseases, specifically psoriasis or rheumatoid arthritis.^[23]

Clinical significance

These days, several

Approved anti-IL-17(R) drugs include: Brodalumab (Siliq), an antibody targeting IL-17 receptor is approved for the treatment of psoriasis.^[25] Ixekizumab and secukinumab approved for plaque psoriasis are antibodies which target IL-17A itself rather than the receptor.^[26][27]

See also

• T helper 17 cell
• IL-17 family

References