7α-Hydroxycholesterol induces monocyte/macrophage cell expression of interleukin-8 via C5a receptor

We investigated effects of 7-oxygenated cholesterol derivatives present in atherosclerotic lesions, 7 alpha-hydroxycholesterol (7 alpha OHChol), 7 beta-hydroxycholesterol (7 beta OHChol), and 7-ketocholesterol (7K), on IL-8 expression. Transcript levels of IL-8 and secretion of its corresponding gene product by monocytes/macrophages were enhanced by treatment with 7 alpha OHChol and, to a lesser extent, 7K, but not by 7 beta OHChol. The 7-oxygenated cholesterol derivatives, however, did not change transcription of the IL-8 gene in vascular smooth muscle cells. 7 alpha OHChol-induced IL-8 gene transcription was inhibited by cycloheximide and Akt1 downregulation, but not by OxPAPC. Expression of C5a receptor was upregulated after stimulation with 7 alpha OHChol, but not with 7K and 7 beta OHChol, and a specific antagonist of C5a receptor inhibited 7 alpha OHChol-induced IL-8 gene expression in a dose dependent manner. Pharmacological inhibitors of PI3K and MEK almost completely inhibited expression of both IL-8 and cell-surface C5a receptor induced by 7 alpha OHChol. These results indicate that 7-oxygenated cholesterol derivatives have differential effects on monocyte/macrophage expression of IL-8 and C5a receptor and that C5a receptor is involved in 7 alpha OHChol-induced IL-8 expression via PI3K and MEK.