IL-17A Signaling in Airway Cells


Pathway Description

IL-17A (also referred to as IL-17) is a member of the family of IL-17 ligands which also includes IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. It is mainly produced by a subset of T cells called TH17. TH17 cells are driven to differentiate by TGF-β, IL-1 and IL-6, while IL-23 is required to expand and stabilize the cell population. IL-17A has also been detected in other cells such as neutrophils and macrophages. While IL-17A is linked to the pathogenesis of diverse autoimmune and inflammatory diseases, it also plays an essential role in host defense against extracellular bacteria and fungi.The presence of IL-17A in the airway lumen is a hallmark of several inflammatory lung disorders, such as chronic obstructive pulmonary disease (COPD) and asthma. Different signaling pathways mediate IL-17A induced gene expression in airway cells such as epithelial and smooth muscle cells. In vivo, IL-17A forms homodimers, binds to and activates a heterodimeric receptor complex consisting of IL-17RC and IL-17RA subunits. The IL-17R complex does not possess intrinsic enzymatic activity but induces signaling via recruitment of signaling intermediates. Airway epithelial cells utilize NF-κB and PI3K/AKT signaling pathways. The PI3K/AKT pathway involves the phosphorylation and activation of JAK kinases upstream of PI3K, while the NF-κB pathway requires ACT-1, a SEFIR-domain containing protein and TRAF-6, an E3 ubiquitin ligase. Together they activate TRAF-1 leading eventually to the activation and nuclear translocation of NF-κB. NF-κB induces transcription of various genes that regulate inflammation, chemotaxis, mucous hypersecretion and antimicrobial activity.

Airway smooth muscle cells are key determinants of asthma due to their ability to contract in response to inflammatory cell products. IL-17A has been shown to activate MAPK and JAK/STAT signaling in these cells. MAPKs (ERK, JNK and p38 MAPK) and JAKs are phosphorylated in response to IL-17A, resulting in the induction of Eotaxin (CCL11). Eotaxin is a chemokine required for eosinophil recruitment and promotion of airway inflammation in asthma. Thus, IL-17A plays a key part in airway inflammatory diseases.