Interleukin 17

Interleukin-17 (IL-17, or IL-17A) is the founding member of a group of cytokines called the IL-17 family. IL-17A, was originally identified as a transcript from a rodent T-cell hybridoma by Rouvier et al. in 1993. Known as CTLA8 in rodents, IL-17 shows high homology to viral IL-17 encoded by an open reading frame of the T lymphotropic rhadinovirus Herpesvirus saimiri.^[1] To elicit its functions, IL-17 binds to a type I cell surface receptor called IL-17R.^[2]

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Members of the IL-17 family

In addition to IL-17A, members of the IL-17 family include IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F. All members of the IL-17 family have a similar protein structure, with four highly conserved cysteine residues critical to their 3-dimensional shape yet they have no sequence similarity to any other known cytokines. Phylogenetic analysis reveals that among IL-17 family members, the IL-17F isoforms 1 and 2 (ML-1) have the highest homology to IL-17A (sharing 55 and 40% amino acid identity to IL-17A respectively), followed by IL-17B (29%), IL-17D (25%), IL-17C (23%), and IL-17E being most distantly related to IL-17A (17%). These cytokines are all well conserved in mammals, with as much as 62–88% of amino acids conserved between the human and mouse homologs.^[3]

Functions of the IL-17 family

Numerous immune regulatory functions have been reported for the IL-17 family of cytokines, presumably due to their induction of many immune signaling molecules. Most notably, IL-17 is involved 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 IL-6, G-CSF, GM-CSF, IL-1β, TGF-β, TNF-α), chemokines (including IL-8, GRO-α and MCP-1) and prostaglandins (e.g. PGE₂) from many cell types (fibroblasts, endothelial cells, epithelial cells, keratinocytes and macrophages). 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 CD4+ T-Cells called T helper 17 (T_h17) cells. As a result of these roles, the IL-17 family has been linked to many immune/autoimmune related diseases including rheumatoid arthritis, asthma, lupus, allograft rejection and anti-tumour immunity. ^[4]

Gene expression of the IL-17 family

The gene for human IL-17 is 1874 base pairs long^[5] and was cloned from CD4+ T cells. Each member of the IL-17 family has a distinct pattern of cellular expression. The expression of IL-17A and IL-17F appear to be restricted to a small group of activated 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.^[4]

Regulation of IL-17 Expression

Much progress has been made in the understanding of the regulation of IL-17. Initially, Aggarwal et al. showed that production of IL-17 was dependent on IL-23.^[6] Later, a Korean group discovered that STAT3 and NF-κB signalling pathways are required for this IL-23-mediated IL-17 production.^[7]. Consistent with this finding, Chen "et al". showed that another molecule, SOCS3, plays an important role in IL-17 production^[8]. In the absence of SOCS3, IL-23-induced STAT3 phosphorylation is enhanced, and phosphorylated STAT3 binds to the promotor regions of both IL-17A and IL-17F increasing their gene activity. In contrast, some scientists believe IL-17 induction is independent of IL-23. Several groups have identified ways to induce IL-17 production both in vitro ^[9] and in vivo^[10][11] by distinct cytokines, called TGF-β and IL-6, without the need for IL-23.^[9][10][11] Although IL-23 is not required for IL-17 expression in this situation, IL-23 may play a role in promoting survival and/or proliferation of the IL-17 producing T-cells. Recently, Ivanov et al. found that the thymus specific nuclear receptor, RORγt, directs differentiation of IL-17-producing T cells.^[12]

Protein Structure of IL-17 Family

IL-17(A) is a 155 amino acid protein that is a disulfide linked, homodimeric, secreted glycoprotein with a molecular mass of 35kDa.^[3]. Each subunit of the homodimer is approximately 15-20 KDa. The structure of IL-17 consists of a signal peptide of 23 amino acids (aa) followed by a 123 aa chain region characteristic of the IL-17 family. An N-linked glycosylation site on the protein was first identified after purification of the protein revealed two bands, one at 15 KDa and another at 20 KDa. Comparison of different members of the IL-17 family revealed four conserved cysteines that form two disulfide bonds.^[5]. 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.^[13].

The crystal structure of IL-17F, which is 50% homologous to IL-17A, revealed that IL-17F is structurally similar to the cysteine knot family of proteins that includes the neurotrophins. The cysteine knot fold is characterized by two sets of paired β-strands stabilized by three disulfide interactions. However, in contrast to the other cysteine 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.^[14].

IL-17 Receptor Family Distribution and Signaling

The IL-17 receptor family consists of five, broadly distributed receptors that present with individual ligand specificities. Within this family of receptors, IL-17R is the best described. IL-17R 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^[3][15][16].

Another member of this receptor family, IL-17RB, binds both IL-17B and IL-17E^[3][16]. Furthermore, it is expressed in the kidney, pancreas, liver, brain and intestine^[3]. IL-17RC is expressed by the prostate, cartilage, kidney, liver, heart and muscle and its gene may undergo alternate splicing to produce a soluble receptor in addition to its cell membrane bound form. Similarly, 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 as yet undefined ligands^[3][16]. The least described of these receptors, IL-17RE, is known to be expressed in the pancreas, brain and prostate^[3].

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^[15]. Transcription factors such as TRAF6, JNK, Erk1/2, p38, AP-1 and NF-κB have been implicated in IL-17 mediated signaling in a stimulation-dependent, tissue-specific manner^[15][16]. 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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