C4b‐binding protein negatively regulates TLR 4/ MD ‐2 response but not TLR 3 response

Recently, we reported a novel function for C4b‐binding protein (C4 BP ) in inhibiting the toll‐like receptor ( TLR )1/2 response by interacting with TLR 2. TLR s share a common structure; hence, we examined the effect of C4 BP on activation of other TLR s— TLR 4 and TLR 3. The results of immunoprecipitation assays suggest that C4 BP interacts with TLR 4/ MD ‐2 but not TLR 3. C4 BP inhibits TLR 4/ MD ‐2‐mediated, but not TLR 3‐mediated, proinflammatory cytokine production and nuclear factor ( NF )‐κB signaling. C4 BP ‐deficient mice show increased interleukin ( IL )‐6 production in response to the TLR 4/ MD ‐2 ligand. A competition assay revealed that C4 BP prevents an interaction between TLR 4/ MD ‐2 and its ligand. These findings indicate that C4 BP binds to cell surface TLR s and inhibits the TLR – TLR ligand interaction, thereby inhibiting TLR activation.