The fungal metabolite cyclonerodiol inhibits IL-4/1L-13 induced Stat6-signaling through blocking the association of Stat6 with p38, ERK1/2 and p300

The IL-4/IL-13/Stat6 pathway is the key driver of asthma pathophysiology. Therefore the development of inhibitors that specifically modulate IL-13/IL-4 or the downstream signaling molecules like Stat6 may be useful as a therapeutic strategy for the treatment of asthma and multiple allergic diseases. We have previously identified the fungal 2,6-cyclofamesane cyclonerodiol as an inhibitor of IL-4 induced Stat6-dependent signaling in the alveolar epithelial cell line A549 using a transcriptional reporter. In this study we investigated the underlying mode of action of cyclonerodiol on the IL-4/IL-13/Stat6 pathway. Cyclonerodiol failed to interfere with activation, nuclear transport or binding of Stat6 to the corresponding consensus sequence on the DNA. Our results showed that cyclonerodiol blocked serine phosphorylation of Stat6 by affecting its association with p38 and Erk1/2. Cyclonerodiol also prevented the recruitment of the transcriptional coactivator p300 and Stat6 acetylation. These findings suggest that cyclonerodiol affects IL-4/IL-13 induced expression of asthma related marker genes by blocking transcriptional activation.