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 macro phages is generally believed to be a significant inductive step in ath erogenesis. Endocytosis of ox-LDL by scavenger receptors (SR) on macro phages is one result of this interaction, as is suppressed expression of several lipopolysaccharide (LPS)-stimulated, inflammatory genes suc h as tumor necrosis factor-alpha (TNF-alpha). Events subsequent to SR ligation, including intracellular signaling events if any, have not be en established, We report here that ox-LDL initiates rapid hydrolysis of phosphatidylinositol 4,5-bisphosphate 2 (PIP2) and intracellular fl uxes of Ca2+ in macrophages, both of which are sensitive to pertussis toxin, ox-LDL also suppresses the LPS-induced binding of macrophage ex tracts 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 i nvolves hydrolysis of PIP2 and which can suppress expression of the TN F-alpha gene by modulating activation of NF kappa B.