title: 27-Hydroxycholesterol and 7alpha-hydroxycholesterol trigger a sequence of events leading to migration of CCR5-expressing Th1 lymphocytes.
abstract: Th1 lymphocytes are predominant in atherosclerotic lesions. However, mechanisms involved in the Th1 predominance are unknown. We have investigated the possibility of Th1 lymphocyte recruitment in a cholesterol-rich milieu. A high cholesterol diet resulted in enhanced expression of CCR5 ligands, including CCL3 and CCL4, but not of proatherogenic CXCR3 ligands, in atherosclerotic arteries of ApoE(-/-) mice. 27-Hydroxycholesterol and 7α-hydroxycholesterol, cholesterol oxides (oxysterols) detected in abundance in atherosclerotic lesions, greatly induced the transcription of CCL3 and CCL4 genes in addition to enhancing secretion of corresponding proteins by THP-1 monocytic cells. However, an identical or even higher concentration of cholesterol, 7β-hydroxycholesterol, and 7-ketocholsterol did not influence expression of these chemokines. Conditioned media containing the CCR5 ligands secreted from THP-1 cells induced migration of Jurkat T cells expressing CCR5, a characteristic chemokine receptor of Th1 cells, but not of Jurkat T cells that do not express CCR5. The migration of CCR5-expressing Jurkat T cells was abrogated in the presence of a CCR5-neutralizing antibody. 27-Hydroxycholesterol and 7α-hydroxycholesterol enhanced phosphorylation of Akt. Pharmacological inhibitors of phosphoinositide-3-kinase/Akt pathways blocked transcription as well as secretion of CCL3 and CCL4 in conjunction with attenuated migration of CCR5-expressing Jurkat T cells. This is the first report on the involvement of cholesterol oxides in migration of distinct subtype of T cells. We propose that 27-hydroxycholesterol and 7α-hydroxycholesterol can trigger a sequence of events that leads to recruitment of Th1 lymphocytes and phosphoinositide-3-kinase/Akt pathways play a major role in the process.
authors.affiliation: Department of Pharmacology, Pusan National University, School of Medicine, 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, Pusan National University, School of Medicine, 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: Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 626-870, Republic of Korea. Electronic address: saeah486@nate.com.
authors.forename: Sae-A
authors.initials: SA
authors.lastname: Lee
authors.affiliation: Laboratory of Microbiology, College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Jeonju, Jeonbuk 561-756, Republic of Korea. Electronic address: vetvirus@chonbuk.ac.kr.
authors.forename: Seong-Kug
authors.initials: SK
authors.lastname: Eo
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: yunyung@ewha.ac.kr.
authors.forename: Yungdae
authors.initials: Y
authors.lastname: Yun
authors.affiliation: Department of Pharmacology, Pusan National University, School of Medicine, 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, Pusan National University, School of Medicine, 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; D045744:Cell Line, Tumor; D002465:Cell Movement; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D054407:Chemokine CCL4 / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000008:administration & dosage; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C515429:CCL3 protein, human; C066507:CCL4 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D006888:Hydroxycholesterols; D019713:Receptors, CCR5; C011724:cholest-5-en-3 beta,7 alpha-diol; C076996:27-hydroxycholesterol; D002784:Cholesterol; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: 27-hydroxycholesterol; 27OHChol; 7-ketocholesterol; 7K; 7α-hydroxycholesterol; 7αOHChol; 7β-hydroxycholesterol; 7βOHChol; Akt inhibitor IV; Akti IV; CHX; Chemokines; Cholesterol oxides (oxysterols); Migration; Th1 lymphocytes; cycloheximide