IL‐33 is clearly expressed in the airway of patients with asthma, but its role in asthma has not yet been fully understood. IL‐17F is also involved in the pathogenesis of asthma. However, the regulatory mechanisms of IL‐17F expression remain to be defined. To further indentify the role of IL‐33 in asthma, we investigated the expression of IL‐17F by IL‐33 in bronchial epithelial cells and its signaling mechanisms.

Bronchial epithelial cells were stimulated with IL‐33. The levels of IL‐17F expression were analyzed using real‐time PCR and ELISA. Next, the involvement of ST2, MAP kinases, and mitogen‐ and stress‐activated protein kinase1 (MSK1) was determined by Western blot analyses. Various kinase inhibitors and anti‐ST2 neutralizing Abs were added to the culture to identify the key signaling events leading to the expression of IL‐17F, in conjunction with the use of short interfering RNAs (siRNAs) targeting MSK1.

IL‐33 significantly induced IL‐17F gene and protein expression. The receptor for IL‐33, ST2, was expressed in bronchial epithelial cells. Among MAP kinases, IL‐33 phosphorylated ERK1/2, but not p38MAPK and JNK. It was inhibited by the pretreatment of anti‐ST2 neutralizing (blocking) Abs. MEK inhibitor significantly blocked IL‐17F production. Moreover, IL‐33 phosphorylated MSK1, and MEK inhibitor diminished its phosphorylation. Finally, MSK1 inhibitors and transfection of the siRNAs targeting MSK1 significantly blocked the IL‐17F expression.

IL‐33 induces IL‐17F via ST2‐ERK1/2‐MSK1 signaling pathway in bronchial epithelial cells. These data suggest that the IL‐33/IL‐17F axis is involved in allergic airway inflammation and may be a novel therapeutic target.