Synthetic peptides representing the N-terminal segment of surfactant protein C modulate LPS-stimulated TNF-alpha production by macrophages.
Surfactant protein C (SP-C) consists of a hydrophobic alpha-helix inserted in pulmonary surfactant membranes, and a more polar N-terminal palmitoylated segment exposed to the aqueous phase. Previously, we showed that SP-C inserted in lipid vesicles interacts with bacterial lipopolysaccharide (LPS) and reduces LPS-elicited responses. As the N-terminal segment of SP-C was the most likely region responsible for these effects, a set of synthetic analogs of this stretch (SPC((1-13)) ) were studied. Binding studies showed that SPC((1-13)) binds LPS to the same extent as porcine SP-C under lipid-free conditions. In the absence of serum, both, palmitoylated and non-palmitoylated analogs enhanced the binding of tritiated LPS to macrophages as well as the LPS-induced production of TNF-alpha by these cells. These effects were reversed in the presence of serum; the analogs reduced the production of TNF-alpha in LPS-stimulated macrophages, probably by interfering with the formation of LPS/CD14/LBP complexes as suggested by analysis of the fluorescence emitted by a FITC derivative of Re-LPS. Our data indicate that water-soluble analogs of the N-terminal segment of SP-C can reduce LPS effects in the presence of serum, and thus might help in the design of new derivatives to fight endotoxic shock and pro-inflammatory events.
Garcia-Verdugo
Ignacio
I
Institut de Biochimie et Biophysique Moléculaire et Cellulaire, UMR-8619 du CNRS, Université de Paris-Sud, Orsay, France.
Garcia de Paco
Elvira
E
Espinassous
Quentin
Q
Gonzalez-Horta
Azucena
A
Synguelakis
Monique
M
Kanellopoulos
Jean
J
Rivas
Luis
L
Chaby
Richard
R
Perez-Gil
Jesús
J
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D036341:Intercellular Signaling Peptides and Proteins; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000276:immunology; D008081:Liposomes; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology*; D037721:Pulmonary Surfactant-Associated Protein C; D011663:Pulmonary Surfactants; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000096:biosynthesis*
D036341:Intercellular Signaling Peptides and Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008081:Liposomes; D010455:Peptides; D037721:Pulmonary Surfactant-Associated Protein C; D011663:Pulmonary Surfactants; C489680:Sftpc protein, mouse; D014409:Tumor Necrosis Factor-alpha