Il 17 Family Proteins

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 Il 17 Family Proteins Background

IL-17 family members

Sequencing of vertebrate species’ genomes revealed that there are at least six IL-17 family members: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. In order to better understand the characteristics of IL-17, the crystal structure of IL-17F was determined. It revealed a tertiary protein structure that is distinct from other interleukins. Although IL-17F adopts a fold similar to that of the cystine knot superfamily of proteins, such as platelet-derived growth factors (PDGFs) and the TGF-β family, there is deviation from the typical cystine knot structure. Specifically, IL-17F contains only two of the three distinctive cystine linkages that lend the family its name. This distinctive folding is likely to be present in other IL-17 members as well. It also hints at a unique receptor structure that is needed to accommodate the ligand.

Of the six members of the IL-17 family, IL-17A and IL-17F are the best characterized. These two may also be the closest related since they are the only members that are encoded adjacent to each other on the same chromosome, while others are encoded on different chromosomes. Specifically, Il17a and Il17f are encoded on mouse chromosome 1 and human chromosome 6. The two members bear 44% homology, compared to other members that are limited to 15-27% homology. IL-17A is the dominant product of Th17 cells and is commonly referred to as IL-17.

IL-17A and IL-17F exist as homodimers but heterodimers of IL-17A-IL-17F have also been observed. These heterodimers are present at higher levels than IL-17A homodimers in human peripheral blood mononuclear cells (PBMC) in vitro, but the in vivo dominant form is undefined. While both are pro-inflammatory, IL-17A and IL-17F do vary subtly in their immunological roles. From studies of Il17a-/- and Il17f-/-, IL-17A is shown to be the major player in autoimmunity. This may be due to more potent and sustained signaling of IL-17A compared to IL-17F. IL-17F induced responses were 10-30 times weaker in terms of downstream gene activation than IL-17A.

As for the rest of the family members, their roles are less well defined. However, they all have been shown to stimulate transcription of similar proinflammatory genes as those stimulated by IL-17A and IL-17F. Additionally, experimental evidence suggests a similar involvement of these cytokines in autoimmunity. For example, increased expression of IL-17B and IL-17C exacerbated collagen-induced arthritis (CIA), while antibodies against IL-17B partially suppressed CIA. IL-17E also has been shown to induce pathological changes such as inflammatory cell infiltration, epithelial hyperplasia and hypertrophy of the liver, heart and lung.

However, IL-17E, also known as IL-25, is somewhat different from IL-17A in that it is produced by Th2 cells, not Th17 cells. Transgenic overexpression of IL-17E promotes Th2 type cytokines, such as IL-4, IL-5, IL-10, and IL-13, in addition to inducing cells and antibodies specializing in allergic responses. The implication of this link to Th2 cells is unknown. These IL-17 family members may become better defined in the future using gene knockouts and characterization of the function of the receptors.


IL-17 function

The primary function of IL-17 is mediating inflammation not adequately handled by cytokines from the Th1 and Th2 subsets. IL-17 protect against extracellular bacterial infections such as Klebsiella pneumoniae and fungal infections such as Candida albicans. IL-17 mediates an adaptive response against pathogens through the recruitment of cells primarily involved in innate responses such as neutrophils, and monocytes and macrophages (M/M). Like IL-17, M/M coordinate the immune system between the innate and adaptive branches of immunity. They are one of the first cells to arrive at the site of injury, where they engulf microbes and present the microbial peptides to the T cells. M/M also release cytokines such as IL-6, IL-1β, and tumor necrosis factor α (TNF-α) at sites of injury to promote inflammation and sequester pathogens at the site of injury. M/M were shown to be responsive to IL-17A, in that upon IL-17A binding, human macrophages have been shown to produce IL-1β and TNF-α. Furthermore, IL-17R is expressed in airway smooth muscle that upon binding to IL-17 induces CXCL8 expression which enhances integrin expression in monocytes and adherence to endothelial cells.

IL-17 mediates a strong proinflammatory tissue response through several mechanisms. Firstly, it induces the production of chemokines such as IL-8, monocyte chemoattractant protein-1 (MCP-1), and growth-regulated oncogene α (Groα) from target cells such as epithelial cells, fibroblasts and endothelial cells. Secondly, IL-17 stimulates local production of IL-6 and PGE2, which further enhances inflammation. Thirdly, it increases the proliferation of M/M from local stromal cells through stimulating the production of hematopoietic cytokine G-CSF and granulocyte macrophage (GM)-CSF in target cells to perpetuate the inflammatory responses. Chemokines, proinflammatory cytokines and M/M and neutrophils, together, act in a positive feedback loop that amplifies the overall inflammatory response. Understandably, deregulation of such a potent cytokine could lead to chronic inflammation and induction of autoimmune diseases.

IL-17 produced from innate sources can also induce secretion of G-CSF from stromal cells and recruitment of neutrophils. IL-17 synergizes with other cytokines such as IL-6 and TNF to promote neutrophil infiltration for elimination of extracellular pathogens. In the lung during Mycobacterium tuberculosis infection, γδ T cells produce IL-17, which enhances adaptive immunity by recruiting Th1 cells and inducing IFNγ production.


The IL-17 receptor family

As there are multiple members of the IL-17 family, so are there multiple subunits comprising the IL-17R family, which consists of five receptor members: IL-17RA to IL- 17RE. IL-17RA is the largest member of the family and is the most defined in structure and signaling. IL-17RA is indispensable in mediating the inflammatory effects of IL-17. For example, IL-17RA KO mice are predisposed to K. pneumoniae and C. albicans infection. IL-17RA KO mice also have increased mortality rates with Toxoplasma gondii infection due to lack of neutrophil trafficking to infection site. It is a signaling subunit used by at least four members of IL-17 family: IL-17A, IL-17F, IL-17D and IL-17E. Binding assays using radiolabeled iodide IL-17 showed that IL-17 binds to IL-17RA with low affinity. This was surprising since IL-17 is capable of inducing biological activity at low concentrations, suggesting that probably other subunits associate with IL-17RA to increase affinity towards the ligand. Indeed, further experiments confirm this. IL-17RA was shown to complex with IL-17RC using fluorescence resonance energy transfer (FRET) and co-immunoprecipitation studies. The exact mechanism of how these receptor subunits interact to form a functional receptor for signaling has not been clarified. However, it does seem that IL-17A behaves like other cytokine receptors, where subunits exist as monomers within the membrane and oligomerize with other subunits upon ligand binding, bringing signaling domains to close proximity to initiate downstream cascades.

expression of IL-17R members differ depending on the tissue type. While the main production of IL-17 is limited to Th17 cells, IL-17 receptors are expressed throughout the body on cells. For instance, IL-17RB is expressed on organs such as the liver and kidneys, as well as Th2 cells, to bind IL-17E. Meanwhile, IL-17RA is highly expressed on hematopoietic cells and poorly expressed on non-hematopoietic cells such as osteoblasts, fibroblasts, endothelial cells and epithelial cells. In contrast, IL-17RC is poorly expressed on hematopoietic cells and highly expressed on non-hematopoietic cells. This differential expression of IL-17R subunits could provide tissue specific signaling of IL-17.