Differential Regulation of Cytokine Production in Macrophages and T Helper 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 kDa. 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.Studies using IL-17A and IL-17F knockout mice have delineated the role of these cytokines in autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA), and inflammatory bowel disease (IBD), as well as allergic diseases such as contact hypersensitivity (CHS) and delayed-type hypersensitivity (DTH). While IL-17A is critical for the development of DTH, CHS, EAE, CIA and arthritis, IL-17F is not only dispensable for the induction of these responses, but also does not play a substantial additive, synergistic or compensatory role to that of IL-17A (PMID: 19144317). IL-17A and IL-17F are produced simultaneously by Th17 cells and bind the same receptors. IL-17A induces the expression of a wide variety of cytokines and chemokines such as IL-3, IL-10, CXCL-1 and CCL2 in macrophages and T helper cells. However, IL-17F plays a marginal role in induction of cytokines in macrophages and almost no role in T helper cells. The lack of involvement of IL-17F in autoimmune responses can be attributed to this low cytokine inducing activity of IL-17F in immune cells. In contrast, IL-17A enhances immune responses by activating T cell priming and induces inflammation by increasing expression of cytokines in macrophages and dendritic cells. This illustrates functional differences between IL-17A and IL-17F in immune responses.