So far, five members of the IL-17 receptor superfamily have been identified, as indicated in Table 1. The various receptor complexes that correspond to each ligand are indicated, although it should be emphasized that in no instance has the stoichiometry been demonstrated definitively. The receptor for IL-17D is unknown, as is the ligand(s) for IL-17RD/SEF or an IL-17RA/IL-17RD pairing if it exists (see Ref 75). FN, fibronectin III-like domain; SEFIR, SEF/IL-17R-related signalling domain; TILL, TIR-like loop; CBAD, C/EBPβ activation domain.

The IL-17R complex is composed of IL-17RA and IL-17RC. Both subunits encode SEFIR domains 59, but a sequence similar to the TIR BB-loop is found only on IL-17RA, termed a TIR-like loop (TILL) 43. IL-17RA engages the SEFIR-containing ACT1 adaptor to mediate a variety of downstream events 62. Specifically, ACT1 is required for recruitment of TRAF6 (and possibly TRAF3), which is an essential upstream activator of the classical NF-κB pathway. It is not clear whether TRAF6 is also required for MAPK activation. Act1^-/- cells fail to upregulate C/EBPβ (LAP and LAP* splice variants) and C/EBPδ as well, another event that might be downstream of NF-κB 58, 63. ACT1, but not TRAF6, is required for IL-17A-induced stabilization of several target mRNAs, particularly those encoding chemokines and cytokines 66. Interestingly, ERK might also be controlled, at least indirectly, by ACT1-independent pathways, as Act1^-/- cells show strong upregulation of ERK phosphorylation 24 hours after IL-17A stimulation 63. ERK mediates rapid phosphorylation of C/EBPβ on Thr-188 61. A second functional domain on IL-17RA is located in the C-terminal region, and is not required for efficient activation of NF-κB or the MAPK pathways. However, deletion of this domain results in impaired alternative translation of C/EBPβ from the LAP isoform to the LAP* isoform 43, and hence was termed the ”C/EBPβ-activation domain” (CBAD). The CBAD is also required for IL-17A-mediated inducible phosphorylation of C/EBPβ on Thr-179, which is mediated by GSK3β 61. B. Comparison of IL-17R and TLR/IL-1R signalling. IL-17R and TLR/IL-1R signalling differ in functional receptor motifs (SEFIR/TILL versus TIR) and proximal adaptors (ACT1 versus MYD88 and TRIF), but converge on common pathways (NF-κB, C/EBP and MAPK). Hence these receptors activate similar, although not identical, panels of downstream genes.

The IL-17R complex contains an undetermined number of IL-17RA and IL-17RC subunits, although studies so far indicate that it might be at minumum trimeric, which is the form shown here. Both IL-17A and IL-17F signal through these subunits, although IL-17A has far higher affinity for IL-17RA than for IL-17RC, whereas IL-17F has a somewhat greater affinity for IL-17RC than for IL-17RA 21. There are multiple anti-cytokine strategies proposed designed to block signalling through the IL-17 receptor 92. Antibodies specific for individual ligands or the individual receptor subunits represent the most straightforward approach. Additionally, soluble IL-17R subunits such as fusions to IgG-Fc have been evaluated in pre-clinical models (reviewed in Ref. 93). Finally, preventing receptor assembly by means of soluble PLAD peptides is another possible avenue for drug development, analogous to approaches used with TNFR signalling 47,50.

References in: 1 12 13 4 6 94 95, 96 59 7, 97 5 52, 98 99, 100 101-103 104 58, 63 105 35 106-108 109 22