Oxidized low density lipoprotein suppresses activation of NF kappa B in macrophages via a pertussis toxin-sensitive signaling mechanism.
The interaction of oxidized low density lipoprotein (ox-LDL) and macrophages is generally believed to be a significant inductive step in atherogenesis. Endocytosis of ox-LDL by scavenger receptors (SR) on macrophages is one result of this interaction, as is suppressed expression of several lipopolysaccharide (LPS)-stimulated, inflammatory genes such as tumor necrosis factor-alpha (TNF-alpha). Events subsequent to SR ligation, including intracellular signaling events if any, have not been established. We report here that ox-LDL initiates rapid hydrolysis of phosphatidylinositol 4,5-bisphosphate 2 (PIP2) and intracellular fluxes of Ca2+ in macrophages, both of which are sensitive to pertussis toxin. ox-LDL also suppresses the LPS-induced binding of macrophage extracts to an NF kappa B sequence oligonucleotide and the LPS-initiated accumulation of RNA specific for TNF-alpha. These latter two effects are pertussis toxin-sensitive. Ligation of SR by ox-LDL thus initiates a pertussis toxin-sensitive signaling pathway in macrophages, which involves hydrolysis of PIP2 and which can suppress expression of the TNF-alpha gene by modulating activation of NF kappa B.
Schackelford
R E
RE
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710.
Misra
U K
UK
Florine-Casteel
K
K
Thai
S F
SF
Pizzo
S V
SV
Adams
D O
DO
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004247:DNA; D006868:Hydrolysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction; D037342:Pertussis Toxin; D011485:Protein Binding; D015398:Signal Transduction; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D010566:Virulence Factors, Bordetella; D004247:DNA; D037342:Pertussis Toxin