7α-Hydroxycholesterol induces inflammation by enhancing production of chemokine (C-C motif) ligand 2

We investigated pro-inflammatory activity of 7-oxygenated cholesterol derivatives present in atherosclerotic lesions. Treatment of THP-1 monocyte/macrophage with 7α-hydroxycholesterol (7αOHChol) resulted in increased gene transcription of CCL2 and production of its corresponding protein. The conditioned medium isolated from THP-1 cells treated with 7αOHChol enhanced migration of monocytic cells, and migration was inhibited in the presence of CCL2-neutralizing antibody. In contrast, 7β-hydroxycholesterol (7βOHChol) or 7-ketocholesterol (7K) did not induce expression of CCL2, and the conditioned medium isolated from THP-1 cells exposed to 7βOHChol or 7K did not affect migration of monocytic cells. 7αOHChol also enhanced production of MMP-9. Inhibition of MEK or PI3K resulted in significantly attenuated expression of CCL2, along with that of MMP-9, induced by 7αOHChol. We propose that elevated concentration of a certain type of 7-oxygenated cholesterol derivative, like 7αOHChol, leads to inflammation via upregulation of CCL2 and MMP-9 in macrophages in the artery, thereby promoting progression of atherosclerosis, and the ERK and the PI3K pathways are involved in the process.