The IL-17E-mediated Th2 responses are inhibited in the absence of

The IL-17E-mediated Th2 responses are inhibited in the absence of either chain.71,74,98 In agreement with

the pre-clinical data signifying a role in Th2 biology, elevated expression of IL-17RB is detected in human asthmatic lung tissue, and the 5661G-A polymorphism within the IL-17RB gene, has been identified to be protective against asthma.64,107 Database mining for proteins homologous to IL-17RA led to the identification of IL-17RC.97 Biochemical analyses demonstrate high-affinity BAY 73-4506 molecular weight interactions between IL-17RC–IL-17A and IL-17RC–IL-17F.66 There have been no reports of IL-17RC binding to other IL-17 family members. Similar to IL-17RA, IL-17RC expression is elevated in patients with RA, emphasizing the click here role of this pathway in autoimmune disease pathology.94,95 Intriguingly, alternative splice variants of IL-17RC have been detected in prostrate cancer tumours, but the function of these proteins is unclear.108,109 The function of IL-17RC has only been reported in the context of IL-17A and IL-17F biology.

In agreement with the essential role for IL-17RC in IL-17A and IL-17F responses, genetic deletion or antibody-mediated blockade of this chain abrogates IL-17A and IL-17F responses such as pro-inflammatory cytokine induction.11,110 Similar to the il17ra−/− mice, il17rc−/−mice display delayed onset and milder disease in the MOG-EAE model, and increased susceptibility to fungal infections.111,112 The biology of these IL-17R family members, which were also identified through database searches, is unknown. Interleukin-17RD was detected in endothelial cells and epithelial

cells (Table 2).113 Similar to IL-17RB and IL-17RC, IL-17RD has also been demonstrated to co-localize and complex with IL-17RA.114 Biochemical data suggest that this interaction mediates IL-17A function, as mutations within the cytoplasmic domain Calpain of IL-17RD prevent IL-17A induction of the 24p3 luciferase reporter.114 Other studies suggest that this receptor may have inhibitory effects, as over-expression suppresses fibroblast growth factor-mediated Ras and phosphatidyl inositol 3-kinase signalling. The significance of IL-17RD in vivo remains to be determined. Likewise, the biology of IL-17RE is undetermined. It has been reported that IL-17C binds to IL-17RE, although the import of this interaction is not understood.7 The specific cellular populations that are IL-17RE+ have not been defined.115 Although multiple splice variants of the IL-17RE gene have been identified, the biological significance of these isoforms is unknown.115 A role in MAPK activation has been detected, but further studies are required to understand the significance of this observation. Although substantial efforts have elucidated the biological functions of this unique family, there is still much to be discovered. In particular, the significance of the newer family members in host defence and inflammation needs to be addressed.

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