Interleukin 17

Source: Wikipedia, the free encyclopedia.
Interleukin 17 family
Identifiers
SymbolIL-17_fam
PfamPF06083
InterProIPR010345
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Chr. 6 p12
Search for
StructuresSwiss-model
DomainsInterPro
Interleukin 17B
Identifiers
SymbolIL17B
Alt. symbolsZCOTO7
Chr. 5 q32-34
Search for
StructuresSwiss-model
DomainsInterPro
Interleukin 17C
Identifiers
SymbolIL17C
Alt. symbolsCX2
Chr. 16 q24
Search for
StructuresSwiss-model
DomainsInterPro
Interleukin 17D
Identifiers
SymbolIL17D
Chr. 13 q11
Search for
StructuresSwiss-model
DomainsInterPro
Interleukin 17E
Identifiers
SymbolIL17E
Alt. symbols
Chr. 14 q11.2
Search for
StructuresSwiss-model
DomainsInterPro
Interleukin 17F
Chr. 6 p12
Search for
StructuresSwiss-model
DomainsInterPro

Interleukin 17 family (IL17 family) is a family of pro-inflammatory

Herpesvirus saimiri. In rodents, IL-17A is often referred to as CTLA8.[4]

The biologically active IL-17 interacts with type I cell surface receptor

interleukin-1.[6][7] Moreover, an activation of IL-17 signalling is often observed in the pathogenesis of various autoimmune disorders, such as psoriasis.[8]

Family members

The IL-17 family in humans comprises

IL17F. IL-17E is also known as IL-25. All members of the IL-17 family have a similar protein structure. Their protein sequences contain four highly conserved cysteine residues. These conserved cysteine residues are critical to the right 3-dimensional shape of the entire protein molecule. To the reference, the members of the IL-17 family do not exhibit a significant sequence homology with other cytokines. Among IL-17 family members, the IL-17F isoforms 1 and 2 (ML-1) have the highest sequence homology with IL-17A (55 and 40%, respectively). They follow by IL-17B, which has 29% similarity to IL-17A, IL-17D (25%), IL-17C (23%), and IL-17E (17%). In mammals, the sequences of these cytokines are highly conserved. For instance, the sequence homology between the corresponding human and mouse proteins is usually between 62–88%.[9]

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

keratinocytes
.

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

allograft rejection, anti-tumour immunity and recently psoriasis,[10] multiple sclerosis,[11] and intracerebral hemorrhage.[12]

Gene expression

The

T cells, and upregulated during inflammation. IL-17B is expressed in several peripheral tissues and immune tissues. IL-17C is also highly upregulated in inflammatory conditions, although in resting conditions is low in abundance. IL-17D is highly expressed in the nervous system and in skeletal muscle and IL-17E is found at low levels in various peripheral tissues.[10]

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

T-cells. Recently, Ivanov et al. found that the thymus specific nuclear receptor, ROR-γ, directs differentiation of IL-17-producing T cells.[20]

Structure

IL-17(A) is a 155-amino acid protein that is a

disulfide bonds.[13] IL-17 is unique in that it bears no resemblance to other known interleukins. Furthermore, IL-17 bears no resemblance to any other known proteins or structural domains.[10]

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

β-strands stabilized by three disulfide interactions. However, in contrast to the other cystine knot proteins, IL-17F lacks the third disulfide bond. Instead, a serine replaces the cysteine at this position. This unique feature is conserved in the other IL-17 family members. IL-17F also dimerizes in a fashion similar to nerve growth factor (NGF) and other neurotrophins.[1]

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.

12-O-tetradecanoylphorbol-13-acetate.[8]

IL-17 promotes psoriasis by contributing to the inflammatory response that damages and overturns the

monocytes to the epidermis.[23] These cells release IL-23 which induce Th17 cells to produce IL-17.[24]

IL-17 interaction with IL-17RA receptors, abundant on the keratinocyte cell surface, incite epidermal cells to increase expression of IL-6,

T regulatory cells to control the behavior of Th17 cells.[24] Reduced regulation allows uninhibited proliferation of Th17 cells and production of IL-17 in psoriatic lesions, augmenting IL-17 signaling.[24] Antimicrobial peptides and IL-8 attract neutrophils to the site of injury where these cells remove damaged and inflamed keratinocyte cells.[21][25][27] New immature DCs are also recruited by CCL20 via chemotaxis where their activation restarts and amplifies the cycle of inflammation.[24][25] IL-17 and additional cytokines released from the influx of neutrophils, T and dendritic cells mediate effects on localized leukocytes and keratinocytes that supports the progression of psoriasis by inciting chronic inflammation.[24]

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

IL-17 and IL-17F cytokines by Th17
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.

alternate splicing to produce a soluble receptor in addition to its cell membrane-bound form. In a similar manner, the gene for IL-17RD may undergo alternative splicing to yield a soluble receptor. This feature may allow these receptors to inhibit the stimulatory effects of their yet-undefined ligands.[9][2] The least-described of these receptors, IL-17RE, is known to be expressed in the pancreas, brain, and prostate.[9]

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.

Erk1/2, p38, AP-1 and NF-κB have been implicated in IL-17 mediated signaling in a stimulation-dependent, tissue-specific manner.[39][2][41]
Other signaling mechanisms have also been proposed, but more work is needed to fully elucidate the true signaling pathways used by these diverse receptors.

References