UC San Diego

Asthma is a disease of the airways for which the pathogenesis is still unknown. Recently, the Interleukin-1 (IL-1) family pair, IL-33 and its receptor ST2, has been implicated in asthma. IL-33 activates both innate and adaptive immune cells and induces the release of TH2 cytokines. IL-33 signals through the adaptor protein, MyD88, which forms complexes with interleukin receptor associated kinases (IRAK) 4 and 2 that auto-phosphorylate and activate mitogen-activated proteins kinases (MAPK) and nuclear factor-[kappa]B (NF-[kappa]B) proteins. To further explore the mechanisms of IL-33, we developed a unique mouse model using IL-33 to replicate an allergic asthma- like phenotype independent of antigen and the adaptive immune system. Next, we wanted to determine if this IL-33 induced asthma-like phenotype could be inhibited. The Rebek laboratory of the Scripps Research Institute synthesized [alpha]-helical mimetics of an IRAK2 domain critical for protein-protein interaction (PPI) between IRAK4 and IRAK2. We found that the lead [alpha]-helical mimetic was able to decrease IL-33 induced NF- [kappa]B activity in vitro. Mice treated with the lead [alpha]- helical mimetic and challenged with IL-33 had attenuated airway hyperresponsiveness and airway inflammation compared to controls. This shows that using [alpha]- helical mimetics to block IL-33 signaling is a possible strategy for asthma therapy. Conclusively, the IL-33 pathway is a promising target in treating asthma, making further understanding of its mechanisms a necessity