Follistatin-related protein/follistatin-like 1 evokes an innate immune response via CD14 and toll-like receptor 4

► This is the first report to clarify how FRP acts in immunity on a molecular level. ► FRP associates with CD14 on the cell surface and triggers TLR4 signaling. ► FRP is considered to be a DAMP, because FRP is one of the endogenous TLR4 agonists. ► Similar to LPS, FRP can induce tolerance to TLR4 signaling in target cells. Follistatin-related protein (FRP)/follistatin-like 1 (FSTL1) has multi-specific binding nature especially with TGF-β superfamily proteins, and thereby modulates organ development. However, its function in immune systems remains unclear. Previously, we reported FRP interacts with CD14, which is known to mediate toll-like receptor 4 (TLR4) signaling. Here, we investigated whether FRP activates TLR4 signaling. Recombinant FRP induced interleukin 6 or interleukin 8 production from target cells in a CD14- and TLR4-dependent manner. Moreover, similar to lipopolysaccharide (LPS), FRP induced tolerance to the second LPS stimulation. FRP has the function of evoking innate immune responses as one of the endogenous TLR4 agonists. FRP physically interacts with CD14 by fluorescence-activated cell sorting (View interaction)