title: 7α-Hydroxycholesterol induces inflammation by enhancing production of chemokine (C-C motif) ligand 2.
abstract: 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.
authors.affiliation: Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 50612, Republic of Korea. Electronic address: lala1647@hanmail.net.
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 50612, Republic of Korea. Electronic address: kimboyoung@pusan.ac.kr.
authors.forename: Bo-Young
authors.initials: BY
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 50612, Republic of Korea. Electronic address: squall0211@hanmail.net.
authors.forename: Yonghae
authors.initials: Y
authors.lastname: Son
authors.affiliation: College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea. Electronic address: youngjung@pusan.ac.kr.
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Jung
authors.affiliation: College of Veterinary Medicine, Bio-Safety Research Institute, Chonbuk National University, Iksan, Jeonbuk 54596, Republic of Korea. Electronic address: vetvirus@chonbuk.ac.kr.
authors.forename: Seong-Kug
authors.initials: SK
authors.lastname: Eo
authors.affiliation: Department of Microbiology & Immunology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 50612, Republic of Korea. Electronic address: ycpark@pusan.ac.kr.
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 50612, Republic of Korea. Electronic address: koanhoi@pusan.ac.kr.
authors.forename: Koanhoi
authors.initials: K
authors.lastname: Kim
mesh_terms: D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000378:metabolism; D017077:Culture Media, Conditioned; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D006888:Hydroxycholesterols; C011724:cholest-5-en-3 beta,7 alpha-diol; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9
keywords: Atherosclerosis; CCL2; Inflammation; MMP-9; Monocyte/macrophage; Oxysterol