Human Interleukin 17 (IL-17), also known as IL-17A and CTLA-8, is a 15-20 kDa, variably glycosylated polypeptide that belongs to the IL-17 family of cytokines (1-5). Its alternate name, CTLA-8, originated from rodent studies where an activated hybridoma was created from the fusion of a mouse cytotoxic and a rat T cell lymphoma cell line. The molecule of interest in this study was assumed to have come from the mouse cytotoxic lymphocyte cell (thus the CTL designation), whereas, in fact, it was a rat lymphocyte molecule. Human IL-17/17A is synthesized as a 155 amino acid (aa) precursor that contains a 23 aa signal sequence and a 133 aa mature region that possesses a cysteine-knot fold (4-6). In both human and mouse, there is one conserved N-linked glycosylation site that likely contributes 5 kDa to its native molecular weight. IL-17A forms both a 32-38 kDa disulfide-linked homodimer, and a 40-45 kDa covalent heterodimer with IL-17F (7-9). Most secreted IL-17A is in the form of the IL-17A:F heterodimer, however, the IL-17A:A homodimer is the most bioactive of the two forms (8). Mature human IL-17A is 61%, 74%, and 99% aa identical to mouse, porcine, and chimpanzee IL-17A, respectively (10-12). Mammalian cells known to produce IL-17 are the CD4+
Th17 T cells, Paneth cells, GR1+
myeloid suppressor cells, CD27-
gamma δ T cells, CD1+
iNKT cells, and CD3-
LTi-like cells (9, 13-17).
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).