Th17-associated cytokines as a therapeutic target for steroid-insensitive asthma

Abstract

Steroid-insensitive asthma is an infrequent but problematic airway disease that presents with persistent symptoms, airflow limitation, or recurrent exacerbations even when treated with steroid-based therapies. Because of unsatisfactory results obtained from currently available therapies for steroid-insensitive asthma, a better understanding of its pathogenesis and the development of new targeted molecular therapies are warranted. Recent studies indicated that levels of interleukin (IL)-17 are increased and both eosinophils and neutrophils infiltrate the airways of severe asthmatics. IL-17 is a proinflammatory cytokine mainly secreted from helper T (Th) 17 cells and is important for the induction of neutrophil recruitment and migration at sites of inflammation. This review focuses on the pathogenetic role of Th17 cells and their associated cytokines in steroid-insensitive asthma and discusses the prospects of novel therapeutic options targeting the Th17 signaling pathway.

Figure 1

Targeting the Th17 pathway. Helper T (Th) 17 cells are derived from naïve CD4⁺ T cells under the control of transforming growth factor (TGF)-β, interleukin (IL)-6, and IL-23 during stimulation by cognate antigen. These cytokines also stimulate Th 17 cells to produce IL-21, which affects Th17 cells themselves to activate a specific transcription factor, RORγt through autocrine regulation. Other proinflammatory cytokines, IL-1β and tumor necrosis factor (TNF)-α, may also promote Th17 development. RORγt regulates both Th17 cell differentiation and production of Th17-signature cytokines, IL-17A, IL-17F, IL-21, and IL-22. Among these cytokines, IL-17A and IL-17F play pivotal roles in the pathogenesis of asthma and share a common receptor subunit, IL-17 receptor A (IL-17RA), and IL-17 receptor C (IL-17RC). Several inhibitors of Th17 pathway are currently under clinical investigation.G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; IL-1R, IL-1 receptor; IL-6R, IL-6 receptor, Treg, regulatory T.