IL-17A and IL-17F contribute protective roles in a healthy functioning gastrointestinal system and can promote the pathogenesis of many diseases, including inflammatory bowel disease, when dysregulated. These cytokines are produced by T-helper 17 (Th17) cells, γδT cells, type 3 innate lymphoid cells (ILC3s), natural killer (NK) cells, NKT cells, neutrophils, mucosal-associated invariant T cells, Paneth cells and mast cells (1, 2).
The intestinal epithelium acts as a barrier against pathogens and, when compromised, can lead to inflammatory bowel diseases. IL-17, which includes IL-17A and IL-17F, plays a crucial role in maintaining the integrity of the intestinal epithelium and mucosal barrier and preventing pathogen invasion (1, 3). These cytokines act on intestinal epithelial cells through the IL-17 receptor, IL-17RA and IL-17RC (4). These receptors engage with the cytoplasmic protein ACT1. ACT1 then recruits and ubiquitinates TNF-receptor associated factor 6 (TRAF6), leading to the activation of downstream signaling pathways, including protein kinase (MAPK), CCAAT-enhancer-binding protein β (C/EBPβ) and nuclear factor κB (NF-κB) pathways. This triggers transcriptional activation of downstream target genes that stimulate antimicrobial peptide production and adaptive immune cell recruitment. They also help maintain barrier integrity by promoting epithelial regeneration following inflammation (5).