Role of IL-17F in Allergic Inflammatory Airway Diseases

The IL-17 family of cytokines contains six members: IL-17 (also known as IL-17A), IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25) and IL-17F. IL-17F, the most recently discovered cytokine in this family, shares strongest homology to IL-17A, a cytokine whose importance has been well documented in autoimmune and inflammatory diseases. IL-17F forms homodimers, binds to and signals via a heterodimeric transmembrane receptor complex consisting of IL-17RC and IL-17RA subunits. This heterodimeric receptor is shared by IL-17A. While IL-17A and IL-17F bind IL-17RC with comparable affinities, IL-17F binds IL-17RA with a far lower affinity than IL-17A (PMID: 19575028).Similar to IL-17A, IL-17F is considered an inflammatory cytokine. It is especially important in the pathogenesis of allergic airway inflammation. IL-17F was originally found in bronchoalveolar lavage cells from allergic asthma patients. Interestingly, a coding region variant (His161Arg) of IL-17F gene, possibly encoding an antagonist for IL-17F, has been found in asthma patients in Japanese populations. IL-17F signal transduction in airway epithelial cells is mediated by adaptors, ACT-1 and TRAF-6. TRAF-6 is an E3 ubiquitin ligase. Ubiquitination of IL-17RA by TRAF-6 is essential for IL-17F signaling, but not for IL-17A signaling. ACT-1 contains a SEFIR-domain and physically associates with IL-17RA through this domain. ERK is activated downstream of ACT-1/TRAF-6 which in turn phosphorylates other kinases such as MSK and p90RSK. Thus, IL-17F increases the expression of various cytokines and chemokines which are involved in neutrophil recruitment to the lung and airway inflammation. IL-17F was found to be a more potent inducer of CXCL5 than IL-17A (PMID: 18411338), a known neutrophil recruiter, indicating that IL-17F may regulate neutrophil recruitment in the lung in response to allergen.Eosinophils are the most important inflammatory effector cells accumulating at sites of allergic inflammation, such as the airway submucosa. Activated eosinophils release cytotoxic molecules that cause tissue damage and chronic remodeling in airways. In eosinophils, IL-17F signaling invokes an ACT-1/TRAF-6 mediated activation of NF-κB and ERK signaling pathways to induce the expression of cytokines and chemokines such as IL-6, IL-8 and CXCL-1, molecules involved in the amplification of inflammatory responses during allergic diseases. In these cells, IL-17F differs from IL-17A in some ways (PMID: 18390747). For example: 1)IL-17F, not IL-17A, can increase eosinophil survival, 2)IL-17F activates the ERK and NF-κB signaling pathways while IL-17A activates the p38 MAPK pathway, and 3) IL-17F and IL-23 act synergistically to produce IL-1β and IL-6, which are critical inducers for Th17 polarization.