IL-17A Signaling in Gastric Cells

IL-17A is the founding member of the family of IL-17 ligands which include IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. It is a disulfide-linked homodimeric glycoprotein consisting of 155 amino acids which binds to and activates a heterodimeric transmembrane receptor complex consisting of IL-17RC and IL-17RA subunits. IL-17A is mainly produced by Th17 cells but it is also known to be secreted by a variety of innate immune cells including macrophages, dendritic cells, NK cells and NKT cells. IL-17A has been linked to the pathogenesis of various autoimmune and chronic inflammatory diseases including inflammatory bowel disease (IBD).Studies show that IL-17A plays a complex role in the regulation of cytokines and chemokines in intestinal epithelial cells in IBD. While IL-17A synergizes with TNF-α to repress the expression of certain TNF-α induced genes such as CXCL10, CXCL11 and CCL5, it synergizes with TNF-α to increase the expression of certain other TNF-α induced genes such as CCL20, CXCL8 and CXCL1. The latter was accomplished by increasing the stability of the target mRNA. Some of these biological actions of IL-17A are mediated in part by EGFR signaling where IL-17A and TNF-α synergistically promote phosphorylation and activation of EGFR, resulting in downstream activation of ERK signaling. Furthermore, transcriptional repression and mRNA stabilization by IL-17A have been shown to depend on ERK and p38 MAPK activation. This complex gene regulation mediated by IL-17A and TNF-α is key to inhibiting expression of Th1-recruiting chemokines while simultaneously increasing the expression of Th17- and neutrophil-recruiting chemokines.Inflammatory processes are also implicated in gastric cancer development. In this context, the contribution of IL-17A versus IL-17F signaling in gastric adenocarcinoma cells has been studied (PMID: 17644350). IL-17A and IL-17F both induce the expression of IL-8. However, IL-17A is a more potent inducer of IL-8 than IL-17F. Also, while IL-17A can activate c-Jun and NF-κB, IL-17F activates only NF-κB to induce IL-8 expression. Thus, IL-17A and possibly IL-17F may contribute to inflammation-associated cancer.