The IL-17 Family of Cytokines in Health and Disease

Abstract

The interleukin 17 (IL-17) family of cytokines contains 6 structurally related cytokines, IL-17A through IL-17F. IL-17A, the prototypical member of this family, just passed the 25^th anniversary of its discovery. Although less is known about IL-17B-F, IL-17A (commonly known as IL-17) has received much attention for its pro-inflammatory role in autoimmune disease. Over the past decade, however, it has become clear that the functions of IL-17 are far more nuanced than simply turning on inflammation. Accumulating evidence indicates that IL-17 has important context- and tissue-dependent roles in maintaining health during response to injury, physiological stress, and infection. Here, we discuss the functions of the IL-17 family, with a focus on the balance between the pathogenic and protective roles of IL-17 in cancer and autoimmune disease, including results of therapeutic blockade and novel aspects of IL-17 signal transduction regulation.

Figure 1:. IL-17R family receptors and ligands

Figure 2:. IL-17 signaling pathways: transduction and amplification.

The IL-17RA and IL-17RC subunits are characterized by two extracellular fibronectin-like domains (FN), and bind to IL-17A, IL-17F and IL-17AF ligands. The intracellular domains encode conserved SEFIR domains that interact with a corresponding SEFIR motif on the adaptor Act1. Both IL-17RA and IL-17RC also have essential “SEFIR-extension” sequences (SEFEX) that are required for functional activity. Act1 additionally contains a TRAF-binding site that enables association with TRAF family proteins. Engagement with TRAF6 drives activation of the classical NF-κB pathway, MAPK:AP1 activation and also activation of Syk kinase:CARMA2 that also activates NF-κB. Collectively these factors trigger transcriptional induction of target genes, TRAF2 and TRAF5 can also be engaged by Act1, and promote a pathway of post-transcriptional mRNA stabilization or through control of multiple RNA binding proteins including HuR and Arid5a. A distal, non-conserved domain in IL-17RA activates the transcription factor C/EBPβ, and has been termed CBAD (C/EBPβ activation domain).

Figure 3:. Current IL-17 or IL-23 targeting biologic therapies

Figure 4:. IL-17 functions in skin

In healthy skin, IL-17 is produced by microbiota-responsive Tc17 cells. Tc17-produced IL-17 regulates microbiota and provides anti-fungal protection. When skin injury breaches the epithelial barrier, IL-17 promotes epithelial cell proliferation. In addition, Tc17 produce tissue repair and immunoregulatory molecules (e.g. amphiregulin, VEGF, IL-10) to promote wound healing. If pathogens such as C albicans become invasive, epithelial injury leads to production of pro-inflammatory cytokines to activate and expand IL-17-producing Th17, Tc17 and γδ T cells. In synergy with TNF, IL-17 now induces heightened production of chemokines to recruit neutrophils, and antimicrobial peptides to combat the infection. In psoriasis, the combined pro-inflammatory and wound-healing effects of IL-17 are chronically activated and amplified, causing pathogenic hyperproliferation of keratinocytes and skin inflammation.

Figure 5:. IL-17 protective and pathologic functions