Polycationic lipids inhibit the pro-inflammatory response to LPS.
Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria. As such, it signals monocytes, macrophages and neutrophils to up-regulate phagocytic functions and to release pro-inflammatory cytokines. Despite the established role of CD14 as the main LPS receptor, the precise nature of the LPS signalling complex and its compartmentalization remain unknown. Interactions of LPS with other cell surface molecules such as TLR-4 and MD-2, and its subsequent internalization are required for LPS signalling. Here, we show that the polycationic lipid LipoFectamine causes inhibition of the LPS-induced MAPK activation and lack of pro-inflammatory cytokine production, despite proper localization of CD14 within lipid rafts and massive LPS internalization. The ability of LipoFectamine to inhibit LPS induced pro-inflammatory responses may be due to uncoupling of CD14 from TLR-4/MD-2 in the LPS signalling complex of mouse macrophages/microglial cells, as suggested by inhibition of LPS-induced concomitant internalization of these surface molecules. Thus, LipoFectamine may be a useful tool to dissect the molecular interactions leading to LPS signalling, and identifies a potential therapeutic strategy for LPS clearance.
Leon-Ponte
Matilde
M
FOCIS Centre for Clinical Immunology and Immunotherapeutics, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada N6A 5K8.
Kirchhof
Mark G
MG
Sun
Tina
T
Stephens
Tracey
T
Singh
Bhagirath
B
Sandhu
Shabaz
S
Madrenas
Joaquín
J
D000818:Animals; D002412:Cations / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D007107:Immune System / Q000187:drug effects* / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D008055:Lipids / Q000494:pharmacology*; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D002412:Cations; D016207:Cytokines; D008055:Lipids; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D020928:Mitogen-Activated Protein Kinases