Oxidized low-density lipoprotein (oxLDL) has been shown to modulate transactivation by the peroxisome proliferator-activated receptor (PPAR)-γ and by nuclear factor-κB (NF-κB). In the present study, the oxLDL signalling pathways involved in NF-κB transactivation were investigated by utilizing a reporter construct driven by three upstream NF-κB binding sites, and various pharmacological inhibitors. OxLDL and its constituent lysophophatidylcholine (lysoPC) induced a rapid and transient increase in intracellular calcium and stimulated NF-κB transactivation in resting RAW264.7 macrophage cells in an oxidation-dependent manner. NF-κB activation by oxLDL or lysoPC was inhibited by inhibitors of protein kinase C or by a chelator of intracellular calcium. Tyrosine kinase or phosphatidylinositol 3-kinase inhibitors did not block NF-κB transactivation. Furthermore, oxLDL-induced NF-κB activity was abolished by PPAR-γ ligands. When the endocytosis of oxLDL was blocked by cytochalasin B, NF-κB transactivation by oxLDL was synergistically increased, while PPAR transactivation was blocked. These results suggest that oxLDL activates NF-κB in resting macrophages via protein kinase C- and/or calcium-dependent pathways, and that this does not involve the endocytic processing of oxLDL. The endocytosis-dependent activation of PPAR-γ by oxLDL may function as a route of inactivation of the oxLDL-induced NF-κB signal.

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