A high affinity receptor for mouse IL-17 has been reported, and appears to be a heteromultimer of IL-17RA and IL-17RC, likely in a 2:1 ratio (1). IL-17RA is a 130 kDa, type I transmembrane glycoprotein that bears no resemblance to members of the cytokine, TNF or immunoglobulin receptor superfamily (2, 10, 13). IL-17RC is also a type I transmembrane protein, approximately 90-95 kDa in size, that shares less than 30% aa identity with IL-17RA (14, 15). Both receptors are needed for IL-17A and IL-17A/F activity. The two receptors appear to form a functional association following ligand binding to IL-17RA (1, 16).
IL-17 is best known for its participation in the recruitment and survival of neutrophils (3, 10, 17, 18). Its induction was initially described to be the result of antigen stimulation of dentritic cells, resulting in IL-23 secretion. In a TCR-independent event, IL-23 induces T cell production of IL-17 (3). Once secreted, IL-17 in the bone marrow would seem to induce stromal/fibroblast expression of both G-CSF and SCF (membrane form), an effect that increases neutrophil differentiation and activation. IL-17 may complement this by directly blocking neutrophil apoptosis, promoting greater circulating neutrophil numbers (17). In the tissues, IL-17 seems to promote neutrophil extravasation, principally through its effects on macrophages and endothelial cells (EC). On macrophages, IL-17 induces TNF-alpha, IL-1 beta and IL-6 production (19). TNF-alpha and IL-1 beta then act on local ECs to induce G-CSF secretion, an effect that is potentiated by IL-17 (20). IL-17 further contributes to neutrophil influx by inducing EC CXC chemokine release and NO production, which may increase vascular permeability (3, 9). IL-17 effects are not limited to neutrophils. In synovial joints, IL-17 upregulates RANKL expression on osteoblasts. This provides a stimulus for osteoclast formation and subsequent bone resorption (18).
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