A high affinity receptor for human IL-17 has been reported, and appears to be a heteromultimer of IL-17RA and IL-17RC, likely in a 2:1 ratio (1, 18). 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, 15). 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 (19, 20). 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, 21, 22).
IL-17 is best known for its participation in the recruitment and survival of neutrophils (14, 15, 23, 24, 25). Its induction was initially described to be the result of antigen stimulation of dendritic cells, resulting in IL-23 secretion. In a T cell receptor-independent event, IL-23 induces T cell production of IL-17 (14). Once secreted, IL-17 in the bone marrow would seem to induce stromal/fibroblast expression of both G-CSF and stem cell factor (membrane form), an effect that increases polymorphonuclear neutrophils (PMN) differentiation and production. IL-17 may complement this by directly blocking neutrophil apoptosis, promoting greater circulating PMN numbers (23). In the tissues, IL-17 would also seem to promote neutrophil extravasation, principally through its effects on macrophages and endothelial cells (EC). On macrophages, IL-17 induces TNF-alpha, IL-1b and IL-6 production (26). TNF-alpha and IL-1b then act on local ECs to induce G-CSF secretion, an effect that is potentiated by IL-17 (27). IL-17 further contributes to PMN influx by inducing EC CXC chemokine release and NO production, which may increase vascular permeability (14, 28). IL-17 effects are not limited to inflammation. In synovial joints, IL-17 upregulates RANKL expression on osteoblasts. This provides a stimulus for osteoclast formation and subsequent bone resorption (24). In conjunction with IL-4 and CD40L, IL-17A also promotes the generation of IgE secreting cells (29). And in white fat, IL-17A inhibits adipocyte differentiation from preadipocytes, and impairs glucose uptake by mature adipocytes (30).
Powered by Bioz
