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.
Duan
Guang-Jie
GJ
Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Zhu
Jiang
J
Wan
Jing-Yuan
JY
Li
Xian
X
Ge
Xiao-Dong
XD
Liu
Li-Mei
LM
Liu
You-Sheng
YS
D055371:Acute Lung Injury / Q000517:prevention & control; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control; D015536:Down-Regulation / Q000187:drug effects; D006737:Horseshoe Crabs; D007249:Inflammation / Q000188:drug therapy*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051218:Lymphocyte Antigen 96 / Q000138:chemical synthesis / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000627:therapeutic use; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; C554344:MD-2 mimetic peptide; D016328:NF-kappa B; D010455:Peptides; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases