title: 27-Hydroxycholesterol up-regulates CD14 and predisposes monocytic cells to superproduction of CCL2 in response to lipopolysaccharide.
abstract: We investigated the possibility that a cholesterol-rich milieu can accelerate response to pathogen-associated molecular patterns in order to elucidate mechanisms underlying aggravation of atherosclerosis after bacterial infection. The consumption of a high-cholesterol diet resulted in enhanced the expression of CD14 in arteries of ApoE(-/-) mice. 27-Hydroxycholesterol (27OHChol), the most abundant cholesterol oxide in atherosclerotic lesions, induced the significant expression of CD14 by THP-1 monocytic cells, but not by vascular smooth muscle cells or Jurkat T cells. Additions of lipopolysaccharide (LPS) to 27OHChol-treated THP-1 monocytic cells resulted in superinduction in terms of the gene transcription of CCL2 and the secretion of its gene product. In contrast, cholesterol did not cause increased the expression of CD14 in the aforementioned cells, and the addition of LPS to cholesterol-treated monocytic cells did not result in enhanced the expression of CCL2. The conditioned medium isolated from THP-1 cells exposed to 27OHChol plus LPS further induced the migration of monocytic cells in comparison with conditioned media obtained from THP-1 cells treated with 27OHChol or LPS alone. Treatment with 27OHChol also resulted in the enhanced secretion of MMP-9 and soluble CD14 (sCD14), and the secretion of sCD14 was blocked by a selective MMP-9 inhibitor. The inhibition of the ERK pathway resulted in significantly attenuated the secretion of sCD14 via mechanisms that were distinct from those by PI3K inhibition. We propose that 27OHChol can prime monocytes/macrophages by up-regulation of CD14 such that LPS-mediated inflammatory reaction is accelerated, thereby contributing to aggravated development of atherosclerotic lesions by enhancing recruitment of monocytic cells after infection with Gram-negative bacteria.
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea. Electronic address: lala1647@hanmail.net.
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea. Electronic address: kimboyoung@pusan.ac.kr.
authors.forename: Bo-Young
authors.initials: BY
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Jeonbuk 570-752, Republic of Korea. Electronic address: vetvirus@chonbuk.ac.kr.
authors.forename: Seong-Kug
authors.initials: SK
authors.lastname: Eo
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea. Electronic address: chidkim@pusan.ac.kr.
authors.forename: Chi-Dae
authors.initials: CD
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea. Electronic address: koanhoi@pusan.ac.kr.
authors.forename: Koanhoi
authors.initials: K
authors.lastname: Kim
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D016905:Gram-Negative Bacterial Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D019169:Jurkat Cells; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D006888:Hydroxycholesterols; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; C076996:27-hydroxycholesterol
keywords: Atherosclerosis; CCL2; CD14; Cholesterol oxides (oxysterols); Lipopolysaccharide; Macrophages