IL-17 Family Cytokines

IL-17 Family Cytokines, Receptors, and Signaling Pathways

The IL-17 cytokine family consists of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E/IL-25, and IL-17F. These proteins are secreted by multiple different cell types and primarily promote pro-inflammatory immune responses. IL-17A was the first member of the IL-17 family of cytokines to be cloned, followed by homology-based cloning of the other five IL-17 family members, which share 16–50% amino acid sequence identity with IL-17A. Members of this cytokine family contain five spatially conserved cysteine residues at their C-terminal ends and form a cysteine-knot fold structure. Members of the IL-17 cytokine family are secreted primarily as disulfide-linked homodimers, with the exception of IL-17B, which is secreted as a non-covalent homodimer and IL-17A/F, which is secreted as a heterodimer.

IL-17 Family Receptors

Signaling by IL-17 family cytokines is mediated by members of the IL-17 receptor family. This family includes five members, IL-17 R/IL-17RA, IL-17B R/IL-17RB, IL-17RC, IL-17RD/SEF, and IL-17RE. These receptor subunits are type I transmembrane proteins that contain two extracellular fibronectin type III-like domains and a cytoplasmic SEF/IL-17R/TIR (SEFIR) domain. Members of the IL-17 receptor family oligomerize to form functional receptor complexes that mediate downstream signaling.

IL-17A

IL-17A signals through a receptor complex consisting of IL-17 RA and IL-17 RC. IL-17A is predominantly expressed by Th17 cells and is involved in promoting immune responses against extracellular bacteria and fungi. Binding of IL-17A to its receptor recruits the intracellular adaptor proteins, ACT1, TRAF-3, and TRAF-6, leading to downstream activation of a series of intracellular kinases that drive the NF kappa B-, AP-1-, and C/EBP-dependent expression of pro-inflammatory cytokines, chemokines, and anti-microbial peptides. While IL-17A signaling is intended to protect the host against invading pathogens, it needs to be tightly regulated as IL-17A overexpression has been shown to be associated with chronic inflammatory disorders, autoimmune diseases, and cancer.

IL-17B

IL-17B is secreted as a noncovalent homodimer and signals through a receptor complex consisting of IL-17B R/IL-17RB and an unknown receptor subunit. IL-17B is primarily produced by neutrophils, germinal center B cells, neurons, and chondrocytes, and has been found to be overexpressed in the inflammatory cartilage of a rheumatoid arthritis mouse model. High level expression of either IL-17 B or its receptor IL-17B R/IL-17RB has also been linked to a poor prognosis in breast, pancreatic, and gastric cancer. Most of what is currently known about the signaling pathways activated downstream of IL-17B R/IL-17RB is based primarily upon activation of the receptor by IL-17E/IL-25, which binds to a receptor complex composed of IL-17RA and IL-17B R/IL-17RB. When both IL-17B and IL-17E/IL-25 are present, IL-17B inhibits the ability of IL-17E/IL-25 to bind to IL-17 RA-IL-17B R/IL-17RB receptor complexes and reduces its ability to promote the expression of pro-inflammatory cytokines in epithelial cells. This suggests that under certain conditions, IL-17B may negatively regulate IL-17E/IL-25 signaling.

IL-17C

IL-17C is primarily produced by epithelial cells and immune cells such as CD4⁺ T cells, dendritic cells, and macrophages at sites of inflammation. IL-17C binds to a receptor complex consisting of IL-17 RA and IL-17 RE. Autocrine signaling by IL-17C in epithelial cells stimulates the production of pro-inflammatory cytokines, chemokines, and anti-microbial peptides and is thought to play a central role in the establishment of protective barriers in the skin and intestine. Similar to IL-17A and IL-17B, overexpression of IL-17C has deleterious effects. IL-17C has been shown to be overexpressed in patients with psoriatic skin lesions and atopic dermatitis. Additionally, it is up-regulated in the synovial fluid of patients with rheumatoid arthritis, in tissue from patients with intestinal bowel disease, and in several forms of cancer.

IL-17D

Similar to other IL-17 family cytokines, IL-17D has the ability to induce the expression of pro-inflammatory cytokines and chemokines, but its receptor and the context in which it functions have yet to be characterized. IL-17D is expressed in a variety of different tissues, including brain, skeletal muscle, adipose tissue, lung, heart, and pancreas. Additionally, it is expressed at low levels in resting CD4⁺ T cells and CD19⁺ B cells, but not in activated immune cell types. As little is currently known about the biological activity of IL-17D, the role that it may play in disease pathogenesis is also not well understood. IL-17D has been detected in rheumatoid nodules of patients with rheumatoid arthritis, but its expression was found to be decreased in psoriatic skin lesions. IL-17D has also been described to be involved in promoting the early immune response to viral infections, and to have anti-tumor effects due to its ability to induce the expression of MCP-1, which promotes the recruitment of natural killer cells and M1 macrophage development at tumor sites.

IL-17E

IL-17E, also known as IL-25, signals through a receptor complex consisting of IL-17 RA and IL-17B R/IL-17RB. IL-17E shares only 16% sequence homology with IL-17A, making it the most divergent member of the IL-17 cytokine family. It is produced by a variety of different cell types including endothelial cells, epithelial cells, T cells, dendritic cells, group 2 ILCs (ILC2 cells), macrophages, and eosinophils. While IL-17E signaling activates intracellular signaling pathways that are similar to IL-17A, IL-17E primarily promotes Th2- and Th9-type immune responses. As a result, IL-17E is involved in providing protection against parasitic helminths and may also contribute to the development of allergic asthma. Although IL-17E has also been suggested to have pathogenic effects in inflammatory skin disorders such as psoriasis and atopic dermatitis, it has also been found to suppress Th17-mediated autoimmune diseases in mouse models of rheumatoid arthritis and multiple sclerosis.

IL-17F

Compared with the other IL-17 family cytokines, IL-17F shares the highest homology with IL-17A. IL-17F is frequently co-expressed with IL-17A, and can either form IL-17F homodimers or heterodimers with IL-17A. Similar to IL-17A, IL-17F homodimers and IL-17A/F heterodimers signal through a receptor complex composed of IL-17RA and IL-17RC. Likewise, they both induce the in vitro expression of a similar set of pro-inflammatory genes as IL-17A, although IL-17F displays reduced potency compared to both IL-17A and IL-17A/F. IL-17F expression has been found to be elevated in patients with atopic dermatitis and psoriasis, as well as in patients with multiple sclerosis and Crohn’s disease.

Bio-Techne offers a wide selection of products for IL-17 family research including R&D Systems™ bioactive recombinant human and mouse proteins for most of the IL-17 family cytokines and receptors, along with single and multianalyte immunoassays for monitoring immune responses. In addition, we offer antibodies against IL-17 family cytokines, receptors, and intracellular signaling molecules that are validated for one or more of the following applications: blocking/neutralization, Western blot, flow cytometry, and immunohistochemistry.