Strictinin has been shown to suppress interleukin (IL)-4-induced signal transducer and activator of transcription (STAT)-6 phosphoiylation, which is a critical event for IgE class switching. However, it is unclear how strictinin inhibits STAT6 activation. Strictinin inhibited STAT6 phosphorylation by suppressing IL-4 receptor a (IL-4R alpha) activation. Strictinin was bound to the cell surface and only localized in non-lipid raft fraction of the cells where IL-4R alpha was also located. In addition, strictinin directly bound to IL-4R alpha and inhibited binding of IL-4 to IL-4R alpha. These results suggest that IL-4R alpha locating in non-lipid raft region is a target molecule for strictinin in inhibiting STAT6 activation. (C) 2014 Elsevier Inc. All rights reserved.