27-Hydroxycholesterol induces recruitment of monocytic cells by enhancing CCL2 production

Deposition of lipids in the intima is followed by infiltration of inflammatory cells, like monocytic cells and T lymphocytes, in atherosclerosis. However, roles of lipids in the infiltration of the inflammatory cells are not clearly defined. We investigated the possible involvement of cholesterol or its catabolites in recruitment of monocytic cells. Consumption of a high cholesterol-diet resulted in enhanced expression of CCL2 in arteries of ApoE(-/-) mice. 27-Hydroxycholesterol, the most abundant cholesterol oxide in atherosclerotic lesions, significantly induced the transcription of CCL2 and enhanced secretion of corresponding protein by THP-1 monocytic cells. However, cholesterol and 7-ketocholesterol did not influence expression of CCL2. Conditioned media containing CCL2 induced migration of monocytic cells, and migration was abrogated in the presence of CCL2-neutralizing antibody. TO-901317, a synthetic LXR agonist, inhibited both production of CCL2 and migration of monocytic cells induced by 27-hydroxycholesterol. Expression of CCL2 induced by 27-hydroxycholesterol was blocked when Akt inhibitor IV was added and when Akt1 was knocked down. We propose that 27-hydroxycholesterol will trigger a sequence of events leading to recruitment of monocytes into atherosclerotic lesions.