Potential Involvement of IL-17F in Asthma

Abstract

The expression of IL-17F is seen in the airway of asthmatics and its level is correlated with disease severity. Several studies have demonstrated that IL-17F plays a pivotal role in allergic airway inflammation and induces several asthma-related molecules such as CCL20. IL-17F-induced CCL20 may attract Th17 cells into the airway resulting in the recruitment of additional Th17 cells to enhance allergic airway inflammation. We have recently identified, for the first time, that bronchial epithelial cells are its novel cell source in response to IL-33 via ST2-ERK1/2-MSK1 signaling pathway. The receptor for IL-17F is the heterodimeric complex of IL-17RA and IL-17RC, and IL-17F activates many signaling pathways. In a case-control study of 867 unrelated Japanese subjects, a His161 to Arg161 (H161R) substitution in the third exon of the IL-17F gene was associated with asthma. In atopic patients with asthma, prebronchodilator baseline FEV1/FVC values showed a significant association with the H161R variant. Moreover, this variant is a natural antagonist for the wild-type IL-17F. Moreover, IL-17F is involved in airway remodeling and steroid resistance. Hence, IL-17F may play an orchestrating role in the pathogenesis of asthma and may provide a valuable therapeutic target for development of novel strategies.

Recombinant HMGB1 A box protein inhibits Th17 responses in mice with neutrophilic asthma by suppressing dendritic cell-mediated Th17 polarization

“…Recent studies indicate that abnormal Th17 polarization in neutrophilic asthma are well associated with the steroid-insensitivity and severity of asthmatics, a better understanding of its pathogenesis and the development of Th17 polarization in neutrophilic asthma will be helpful to currently available therapies for steroidinsensitive or severe asthma [25]. Here we show for the first time that rHMGB1 A box, which is an antagonist for HMGB1, represses HMGB1 expression and acts on DCs to attenuate the local Th17 response following allergic airway inflammation.…”

Different Bla‐g T cell antigens dominate responses in asthma versus rhinitis subjects

“…we employed a transcriptomic/proteomic approach with Bla-g extract and sera from Bla-g sensitized individuals to find the “missing” allergens. We previously used a similar approach in TG allergy to discover novel antigens associated with T cell reactivity (20,25,26). Here, we identified 16 novel Bla-g antigens (NBGA) that had IgE and/or IgG reactivity in Bla-g sensitized serum, and re-identified additional antigens recently described by others (15,27,39).…”

“…Allergen-specific T cell responses are usually dominated by T H 2 type responses, with IL-5 secreted at the highest levels, followed by IL-13, IL-4, and IL-9 (23,24), although involvement of different T helper subsets has also been reported. Elevated T H 17 cells have been described, particularly in the context of asthmatic reactions, as IL-17F production has been reported as increased in numerous asthmatic states (25,26). T R 1 cells secreting IL-10 have been implicated in negative regulation of T cell allergic responses (27).…”

Effects of diesel exhaust particle exposure on a murine model of asthma due to soybean

“…The absence of the most important Th2 mediators, and the significant increases in Th17-related cytokines, suggest that a Th17-mediated response might be the mechanism underlying the increases in AHR and in both neutrophilic and even eosinophilic pulmonary inflammation. Th17 cells IL-17A and IL-17F are usually associated only with neutrophilic inflammation [18,21,24], but as our results and previous literature reports suggest, they may have multiple forms of biological activity over bronchial epithelial cells [18,20,21,39], airway smooth muscle cells, fibroblasts, endothelial cells [18,21] and even directly over eosinophils [18,21,40]. Eosinophilia of the airway is a phenomenon associated with Th2 allergen-driven inflammation and with the presence of IL-5 produced by Th2 cells, but in fact, the eosinophils themselves are among the main producers of IL-5 [40].…”