Interleukin 17
Interleukin 17 family | |||||||||
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Identifiers | |||||||||
Symbol | IL-17_fam | ||||||||
Pfam | PF06083 | ||||||||
InterPro | IPR010345 | ||||||||
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Chr. 6 p12 | |||||||
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Interleukin 17B | |||||||
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Identifiers | |||||||
Symbol | IL17B | ||||||
Alt. symbols | ZCOTO7 | ||||||
Chr. 5 q32-34 | |||||||
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Interleukin 17C | |||||||
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Identifiers | |||||||
Symbol | IL17C | ||||||
Alt. symbols | CX2 | ||||||
Chr. 16 q24 | |||||||
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Interleukin 17D | |||||||
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Identifiers | |||||||
Symbol | IL17D | ||||||
Chr. 13 q11 | |||||||
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Interleukin 17E | |||||||
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Identifiers | |||||||
Symbol | IL17E | ||||||
Alt. symbols | Chr. 14 q11.2 | ||||||
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Interleukin 17F | |||||||
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Chr. 6 p12 | |||||||
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Interleukin 17 family (IL17 family) is a family of pro-inflammatory
The biologically active IL-17 interacts with type I cell surface receptor
Family members
The IL-17 family in humans comprises
Function
Numerous immune regulatory functions have been reported for the IL-17 family of cytokines, presumably due to their induction of many immune signaling molecules. The most notable role of IL-17 is its involvement in inducing and mediating proinflammatory responses. IL-17 is commonly associated with allergic responses. IL-17 induces the production of many other cytokines (such as
The release of cytokines causes many functions, such as airway remodeling, a characteristic of IL-17 responses. The increased expression of chemokines attracts other cells including neutrophils but not eosinophils. IL-17 function is also essential to a subset of
Gene expression
The
Much progress has been made in the understanding of the regulation of IL-17. At first, Aggarwal et al. showed that production of IL-17 was dependent on
Structure
IL-17(A) is a 155-amino acid protein that is a
The crystal structure of IL-17F, which is 50% homologous to IL-17A, revealed that IL-17F is structurally similar to the cystine knot family of proteins that includes the
Role in psoriasis
Recent work suggests the IL-23/IL-17 pathway plays a major role in the autoimmune disorder psoriasis.[8][21][22] In this condition, immune cells react to inflammatory molecules released within the skin around the joints and scalp.[21] This response causes the epidermal cells to recycle more rapidly than usual, which leads to the formation of red, scaly lesions and chronic skin inflammation.[22][23] Analysis of biopsies taken from lesions of psoriasis patients show an enrichment of cytotoxic T cells and neutrophils containing IL-17.[21][24][25] This indicates an excessive infiltration of pro-inflammatory immune cells and IL-17 cytokines are associated with the development of psoriasis.
Studies conducted in mice demonstrate that removing either IL-23 or IL-17 decreases the progression of psoriasis.
IL-17 promotes psoriasis by contributing to the inflammatory response that damages and overturns the
IL-17 interaction with IL-17RA receptors, abundant on the keratinocyte cell surface, incite epidermal cells to increase expression of IL-6,
Role in asthma
The IL-17F gene was discovered in 2001 and is located on chromosome 6p12. Notably, among this family, IL-17F has been well characterized both in vitro and in vivo and has been shown to have a pro-inflammatory role in asthma. IL-17F is clearly expressed in the airway of asthmatics and its expression level is correlated with disease severity. Moreover, a coding region variant (H161R) of the IL-17F gene is inversely associated with asthma and encodes an antagonist for the wild-type IL-17F. IL-17F is able to induce several cytokines, chemokines and adhesion molecules in bronchial epithelial cells, vein endothelial cells, fibroblasts and eosinophils. IL-17F utilizes IL-17RA and IL-17RC as its receptors and activates the MAP kinase-related pathway. IL-17F is derived from several cell types such as Th17 cells, mast cells and basophils, and shows a wide tissue expression pattern including lung. Overexpression of IL-17F gene in the airway of mice is associated with airway neutrophilia, the induction of many cytokines, an increase in airway hyperreactivity, and mucus hypersecretion. Hence, IL-17F may have a crucial role in allergic airway inflammation and have important therapeutic implications in asthma.[29]
Therapeutic target
Because of its involvement in immune regulatory functions, IL-17 inhibitors are being investigated as possible treatments for autoimmune diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease.[30][31][32] In January 2015, the FDA approved the use of secukinumab (trade name Cosentyx), an IL-17 inhibiting monoclonal antibody, for the treatment of moderate to severe plaque psoriasis.[33] In addition, Cosentyx has been approved in Japan for use in treating psoriatic arthritis.[34] The anti-IL-23 antibody ustekinumab can also be used to effectively treat psoriasis by indirectly reducing IL-17.[35]
Based on emerging evidence from animal models, IL-17 has been suggested as a target for anti-inflammatory therapies to improve recovery post-stroke[36] and to reduce the formation of skin cancer.[37] IL-17 has also been implicated in multiple sclerosis.[11]
The active form of
cells.Receptors
The IL-17 receptor family consists of five, broadly distributed receptors (IL-17RA, B, C, D and E) that present with individual ligand specificities. Within this family of receptors, IL-17RA is the best-described. IL-17RA binds both IL-17A and IL-17F and is expressed in multiple tissues: vascular endothelial cells, peripheral T cells, B cell lineages, fibroblast, lung, myelomonocytic cells, and marrow stromal cells.[9][39][2] Signal transduction for both IL-17A and IL-17F requires the presence of a heterodimeric complex consisting of both IL-17RA and IL-17RC and the absence of either receptor results in ineffective signal transduction. This pattern is reciprocated for other members of the IL-17 family such as IL-17E, which requires an IL-17RA-IL-17RB complex (also known as IL-17Rh1, IL-17BR or IL-25R) for effective function.[40]
Another member of this receptor family, IL-17RB, binds both IL-17B and IL-17E.
Signal transduction by these receptors is as diverse as their distribution. These receptors do not exhibit a significant similarity in extracellular or intracellular amino acid sequence when compared to other cytokine receptors. Other signaling mechanisms have also been proposed, but more work is needed to fully elucidate the true signaling pathways used by these diverse receptors.
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