IL-17 Family Ligand Review

The interleukin-17 (IL-17) family consists of a subset of cytokines that participate in both acute and chronic inflammatory responses. Since the discovery of IL-17A (also called IL-17 or CTLA8) in 1993, five other members of IL-17 family IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F have been identified based on amino acid sequence homology.

Below will briefly introduce each IL-17 family ligand and their functions, including interleukin-17A (IL-17A), interleukin-17B (IL-17B), interleukin-17C (IL-17C), interleukin-17D (IL-17D), interleukin-17E (IL-17E) and interleukin-17F (IL-17F).

Interleukin-17 Family: IL-17A

IL-17A, the most widely investigated cytokine of IL-17 family, is a pro-inflammatory cytokine that plays an essential role in host defense against microbial infections and is implicated in various inflammatory conditions such as autoimmune diseases, metabolic disorders, and cancer.

IL-17A is a signature cytokine of T helper 17 (Th17) cells. Differentiation of naïve CD4+ T cells to Th17 cells is triggered and tightly controlled by a set of cytokines that include IL-6, IL-1β, IL-21, IL-23, and TGFβ, which leads to the activation of RORγt to enable Th17 programming.

Though Th17 cells were thought as a major source of IL-17A, IL-17A can also be produced by other cell types, the most prominent of which are the innate immune cell populations. IL-17 producing innate immune cells mediate the rapid release of IL-17A in response to pathogens or tissue injury. For example, γδ T cells express pattern recognition receptors (PRRs) such as dectin-1 and Toll-like receptor 2 (TLR2), which allow for rapid IL-17 production in response to bacteria encounter. LTi cells, key components of the machinery required for the construction of the lymphoid structures, produce IL-17A rapidly after challenge with the yeast cell wall product zymosan. IL-17A is also produced by a subset of CD8+ T cells, known as Tc17 cells which can participate in host defense against viruses and contribute to autoimmunity.

Interleukin-17 Family: IL-17B

IL-17B was detected in several organs with high expression in chondrocytes and neurons. IL-17B was reported to bind to IL-17RB, though with lower affinity than IL-25 and stimulated the production of TNF-α and IL-1β by the monocytic cell line, THP-1. IL-17B was highly expressed in the cartilage derived from the paws of collagen-induced arthritis mice, suggesting a potential pro-inflammatory role in disease processes.

Interleukin-17 Family: IL-17C

IL-17C is mainly produced by epithelial cells and was recently found to be important in promoting cytokines and anti-microbial peptides production in the gastrointestinal tract.

Similar to IL-17A, IL-17C is implicated in protection against microbial infection as well as in the pathogenesis of autoimmune disease including psoriasis and multiple sclerosis. IL-17C signals through the IL-17RA/IL-17RE receptor complex and Act1 to promote innate host defense and regulate the intestinal inflammation and barrier function.

Mice lacking IL-17C are partially resistant to experimental autoimmune encephalomyelitis (EAE). NFκB and MAPK pathways were activated by IL-17C in colon epithelial cells but not in IL-17RE deficient cells.

Interleukin-17 Family: IL-17D

IL-17D was detected in several organs, whereas in immune cells, IL-17D is only expressed in resting CD4+ T cell and CD19+ B cells. The biological function of IL-17B and IL-17D are still poorly understood. The receptor for IL-17D has yet to be solved.

Interleukin-17 Family: IL-17E

IL-17E is produced by Th2 cells, cecal patch CD4+ and CD8+ T cells, mast cells, and eosinophilsI. IL-17E enhances Th2 cell immune responses by inducing Th2 cell cytokines such as IL-4, IL-5, and IL-13 in auxiliary cells and induces IgE production and eosinophilia, contributing to the host defense against nematodes and allergic disorders.

The heterodimer consisting of IL-17RA and IL-17RB serves as the receptor for IL-17E. Like IL-17RA, Act1 is recruited to the SEFIR domain of IL-17RB through the interaction of SEFIR between IL-17RB and Act1 after IL-17E bindings. In contrast to IL-17RA, the cytoplasmic TRAF6-binding motif of IL-17RB directly associates with TRAF6 irrespective of IL-17E binding and activates NF-kB upon IL-17E binding.

Interleukin-17 Family: IL-17F

Sharing the greatest sequence homology (56%) with IL-17A, IL-17F signals through the IL-17RA/IL-17RC receptor complex, though IL-17F binds to IL-17RA with 100–1000 times lower affinity than does IL-17A, while the binding affinities for IL-17RC is comparable between the two cytokines.

Human IL-17F is located adjacent to IL-17A on the chromosome 6, and is produced by similar cells, often in conjunction with IL-17A. Crystal structures have revealed that while IL-17A and IL-17F can form IL-17A/A or IL-17F/F homodimers, IL-17A/F heterodimers are also formed. Though some studies have indicated that IL-17A and IL-17F may have disparate roles in inflammation, the aspects that distinguishes the two cytokines have remained largely elusive.

References

1. Gu, C., Wu, L., & Li, X. (2013). IL-17 family: cytokines, receptors and signaling. Cytokine, 64(2), 477-485.
2. Iwakura, Y., Ishigame, H., Saijo, S., & Nakae, S. (2011). Functional specialization of interleukin-17 family members. Immunity, 34(2), 149-162.