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

Abstract

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.

• Authors: Guang-Jie Duan, Jiang Zhu, Jing-Yuan Wan, Xian Li, Xiao-Dong Ge, Li-Mei Liu, You-Sheng Liu
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 10 Issue 9 Pg. 1091-100 (Sep 2010) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 20601183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2010 Elsevier B.V. All rights reserved.

Chemical References

• Lipopolysaccharide Receptors
• Lipopolysaccharides
• Lymphocyte Antigen 96
• MD-2 mimetic peptide
• NF-kappa B
• Peptides
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• Mitogen-Activated Protein Kinases

Topics

• Acute Lung Injury (prevention & control)
• Animals
• Chemical and Drug Induced Liver Injury (prevention & control)
• Down-Regulation (drug effects)
• Horseshoe Crabs
• Inflammation (drug therapy)
• Lipopolysaccharide Receptors (metabolism)
• Lipopolysaccharides (immunology)
• Lymphocyte Antigen 96 (chemical synthesis, therapeutic use)
• Macrophages (drug effects)
• Male
• Mice
• Mice, Inbred BALB C
• Mitogen-Activated Protein Kinases (antagonists & inhibitors)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Peptides (chemical synthesis, therapeutic use)
• Toll-Like Receptor 4 (metabolism)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)