Toll-like receptor 4 (TLR4) is activated by lipopolysaccharide (LPS), with LPS-binding protein, to initiate an innate immune response. Alternatively, hypoxia or ischemia/reperfusion can trigger signaling through TLR4. TAK-242 is a cell-permeable inhibitor of TLR4 signaling, blocking LPS-induced production of NO, TNF-α, IL-6, and IL-1β in macrophages with IC50 values of 1-11 nM. It does not affect signaling through other TLRs. TAK-242 is effective in vivo, suppressing the production of NO, TNF-α, IL-6, and IL-1β in mice treated with LPS when given intravenously. Mechanistically, TAK-242 acts by selectively binding TLR4 and preventing its association with adaptor proteins that are essential for signal transduction. TAK-242 is used to study signaling through TLR4 in a variety of pathologies, including sepsis and ischemia/reperfusion injury.
