A synthetic MD-2 mimetic peptide attenuates lipopolysaccharide-induced inflammatory responses in vivo and in vitro.

Myeloid differentiation protein-2 (MD-2), a secreted glycoprotein that binds to both lipopolysaccharide (LPS) and toll like receptor 4 (TLR4), contributes to the fine ligand recognition and signaling activation on LPS-induced inflammation. Here we synthesized a novel MD-2 mimetic peptide (MDMP), derived from the putative LPS-binding domain and TLR4-binding domain of MD-2, and found that MDMP dose-dependently bound to LPS and inhibited LPS-activated Limulus amebocyte lysate (LAL). Pretreatment with MDMP dampened LPS-induced inflammatory responses in RAW264.7 cells, including down-regulation of TLR4-MD-2 complex on the cell surface, suppression of LPS binding to the cells, inhibition of mitogen-activated protein kinase (MAPKs) and nuclear factor kappa B (NF-kappaB) activation, reduction of tumor necrosis factor-alpha (TNF-alpha) production. Further, in vivo pretreatment with MDMP markedly protected against LPS-induced acute lung injury and liver injury, as indicated by the notable reduction of lethality, inflammatory responses and TNF-alpha production. These results demonstrate that MDMP attenuates LPS-induced inflammatory responses in vivo and in vitro, and suggests that MDMP may be useful in the treatment of inflammation associated with LPS.