The name of IL-17 was first proposed by Yao et al. [1] in 1995 when they discovered that an open reading frame of the T lymphotropic herpesvirus saimiri gene 13 (HSV13) exhibits 58 % homology with a previously cloned molecule, mouse cytotoxic T lymphocyte-associated protein 8 (CTLA-8) [2]. Recombinant HVS13 and CTLA-8 stimulate transcription factor NFκB activity and IL-6 secretion in fibroblasts and co-stimulate T cell proliferation. A novel cytokine receptor was also isolated and shown to bind both HVS13 and CTLA-8. Therefore, mouse CTLA-8 was named as IL-17, HVS13 as viral IL-17, and the newly cloned cytokine receptor as IL-17 receptor (IL-17R) [1]. Human IL-17 shares 72 % homology with HSV13 and 62 % with mouse IL-17 [3]. Subsequently, by homology-based cloning another 5 cytokines were identified to belong to the IL-17 gene family [4, 5, 6, 7]. The prototypic member IL-17 was renamed as IL-17A and the others as IL-17B through to F (see Table 2.​1) [8].

IL-17E was found to be identical to IL-25, which was described by an independent group [9]. All IL-17 cytokines are homodimeric glycoproteins linked by a disulfide bond except IL-17B, which forms a noncovalent homodimer. All show conservation in their c-terminal region, with five spatially conserved cysteine residues accounting for a characteristic cysteine-knot formation. Of these members, IL-17A and IL-17F are most closely related and share 55 % amino acid sequences. IL-17A and IL-17F also form a heterodimer, IL-17A/F, which exerts similar functions to those of IL-17A and IL-17F (see Table 2.​1) [10, 11, 12]. Homology with IL-17A for IL-17B, IL-17D, and IL-17C is in the order of 29 %, 25 %, and 23 %, respectively, and IL-17E is most distant and with only 19 % homology with IL-17A [8].

IL-17 receptor (IL-17R) is also a unique cytokine receptor family [1] with five members identified to date, namely, IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE (see Table 2.​1) [13]. All these IL-17 receptors contain extracellular domains composed of fibronectin type III (FnIII) domains and cytoplasmic similar expression to fibroblast growth factor (SEF) genes–IL-17R (SEFIR) domains that are loosely homologous to Toll/IL-1R domains [14, 15]. Several studies have shown that IL-17RA serves as a common receptor to mediate signals for several members of the IL-17 family (Fig. 1.1) [16, 17, 18, 19, 20, 21, 22, 23].

Indeed, the major IL-17RA interacting residues are identical among all IL-17 cytokines [24]. But IL-17RA does not bind all ligands with an equal affinity. IL-17RA has high affinity for IL-17A, about hundredfold weaker affinity for IL-17F, an intermediate affinity for IL-17A/F, and much weaker affinities for IL-17B, IL-17C, IL-17D, and IL-17E [4, 5, 16, 17, 19, 22, 25]. Interestingly, IL-17RA pairs with other IL-17Rs to form functional heterodimeric receptor complexes. This is apparently determined by the ligands, IL-17 cytokines. For example, the homodimeric IL-17A or IL-17F disfavors binding of a second molecule of IL-17RA, but selects IL-17RC to form IL-17RA-RC complex (Fig. 1.1) [24]. Similarly, other IL-17 cytokines bind their primary receptors and recruit IL-17RA to form a functional heterodimeric receptor complex. IL-17A and IL-17F and IL-17A/F bind to receptor complex IL-17RA-RC, IL-17C to IL-17RA-RE, and IL-17E (IL-25) to IL-17RA-RB (Fig. 1.1) [13]. The redundant activities of IL-17A and IL-17F are partially attributed to their binding to the same IL-17RA-RC receptor complex, and yet the distinct activities of the two cytokines may be due to the different binding affinities to the receptor complex [26]. Both components of the heterodimeric receptor complex are required for signaling. For instance, deficiency of either IL-17RA or IL-17RC can completely abolish the inflammatory function of IL-17A and IL-17F [12, 21, 27, 28].

The proinflammatory and host defense effects of IL-17A and IL-17F are executed chiefly by activation of NFκB and MAPK pathways. A signal from IL-17R is first relayed by a cytosolic protein, signaling adaptor, called Act1 (NFκB activator 1, also known as CIKS) (Fig. 1.2) [29].

Act1 is essential for IL-17 signal transduction. Deficiency of Act1 results in a loss of IL-17-dependent NFκB activation and proinflammatory cytokine production [29, 30]. Upon ligand stimulation of IL-17R, Act1 is recruited to the IL-17R complex. Act1 also contains a SEFIR domain, which binds to the SEFIR region of IL-17R through homotypic interactions [13, 31]. The activated Act1 then binds tumor necrosis factor-associated factor (TRAF)-6 via a TRAF binding domains of Act1 (Figs. 1.1 and 1.2). TRAF6 mediates further downstream cascade interactions to lead to activation of NFκB, MAPK, and C/EBP pathways and the activation of target genes [13].

The importance of Act1 in autoimmunity and inflammatory diseases has been demonstrated in animal models of inflammatory diseases. For instance, mice with deficiency of Act1 have reduced demyelination in a cuprizone-induced multiple sclerosis (MS) model, which is known to be mediated by IL-17 signaling [32]. Act1-deficient mice are protected from collagen-induced arthritis (CIA) [33]. These data suggest that Act1 is a candidate target for therapeutic intervention in human inflammatory diseases.

As in other cytokine signaling, IL-17/IL-17R signaling is also finely regulated. Many regulators have been described to involve positive and negative regulation of the IL-17/IL-17R signaling pathway at various stages [13]. Modulation of these regulatory factors is potentially of therapeutic benefit. Soluble IL-17RA, IL-17RB, and IL-17RC naturally exist and may function as decoy receptor to regulate IL-17–IL-17R signaling in vivo. Indeed, fused with immunoglobulin G (IgG) Fc fragment, soluble IL-17RA (IL-17RA-Fc) is able to suppress IL-17A signaling in cultured cells; IL-17RC-Fc suppresses the effect of IL-17A and IL-17F [27], and IL-17RB-Fc is able to block IL-17E signaling [34]. These soluble receptor-Fc fusion proteins are highly likely to be evaluated as therapeutic agents (Fig. 5.1b).

Signaling through the IL-17R complex can influence function of other IL-17 cytokines. Chang et al. [17] observed that IL-17C is highly expressed in the central nervous system of mice with experimental autoimmune encephalomyelitis (EAE). IL-17C knockout mice exhibited a striking reduction of incidence and severity of EAE along with reduction of Th17 cells [17]. IL-17C signaling through IL-17RA-RE [17, 18, 19] further increases IL-17RE expression on Th17 cells and increases IL-17A, IL-17F, and IL-22 production. Skin keratinocytes and intestine epithelial cells constitutively express IL-17RE and can respond to IL-17C [18, 19]. These findings indicate that IL-17C may be another target for therapy in Th17-mediated inflammatory diseases, but caution needs to be taken for its protective effect in intestines.