Differential Regulation of Cytokine Production in Intestinal Epithelial Cells by IL-17A and IL-17F

IL-17A and IL-17F belong to the family of IL-17 ligands, the other members of which include IL-17B, IL-17C, IL-17D and IL-17E. These cytokines consist of 163-202 amino acids with molecular masses of 20-30 kD. They share four conserved cysteine residues at the C-terminal region that may participate in the formation of intermolecular disulfide linkages. IL-17A and IL-17F are primarily produced by a subset of T cells called Th17 and are highly homologous. They share certain similarities in their mode of signal transduction. They both form homodimers to signal via a heterodimeric receptor complex consisting of IL-17RC and IL-17RA subunits suggesting that they might share biological functions. IL-17A and IL-17F have been linked to cytokine and chemokine production in various inflammatory and/or autoimmune diseases, as well as being involved in the production of antimicrobial peptides against pathogenic bacteria.IL-17A and IL-17F knockout studies have shown that both ligands are important for immune responses and host defense mechanisms directed against bacterial infection. In intestinal epithelial cells, they produce a range of inflammatory cytokines, chemokines and antimicrobial peptides. While expression of some chemokines such as CXCL1, CCL5, CCL2 and GM-CSF is regulated by both IL-17A and IL-17F, expression of IFN-γ, TNF-α, IL-12, IL-3 and IL-1α is exclusively regulated by IL-17A. IL-17A and IL-17F both produce the antimicrobial peptides HBD-1, HBD-2 and HBD-3 (PMID: 19144317). However, defense mechanisms against S. aureus and C. rodentium infection differ between the two cytokines. While either IL-17A or IL-17F is sufficient for protection against S. aureus, both are required for protection against C. rodentium. Further, IL-17F is more important than IL-17A in protecting colonic epithelial cells from splenomegaly and colon hypertrophy, which are associated with severe colonic inflammation in C. rodentium infection. Thus, while IL-17A and IL-17F are similar, they play distinct roles in response to microbial challenge.