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      27-Hydroxycholesterol and 7alpha-hydroxycholesterol trigger a sequence of events leading to migration of CCR5-expressing Th1 lymphocytes.

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          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.

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          Author and article information

          Journal
          Toxicol. Appl. Pharmacol.
          Toxicology and applied pharmacology
          1096-0333
          0041-008X
          Feb 1 2014
          : 274
          : 3
          Affiliations
          [1 ] Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 626-870, Republic of Korea. Electronic address: lala1647@hanmail.net.
          [2 ] Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 626-870, Republic of Korea. Electronic address: kimboyoung@pusan.ac.kr.
          [3 ] Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 626-870, Republic of Korea. Electronic address: saeah486@nate.com.
          [4 ] 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.
          [5 ] Department of Life Science, Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: yunyung@ewha.ac.kr.
          [6 ] Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 626-870, Republic of Korea. Electronic address: chidkim@pusan.ac.kr.
          [7 ] Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 626-870, Republic of Korea. Electronic address: koanhoi@pusan.ac.kr.
          Article
          S0041-008X(13)00560-7
          10.1016/j.taap.2013.12.007
          24370436
          213b76d0-f661-4df1-9492-e2eee4bc7efe
          Copyright © 2013 Elsevier Inc. All rights reserved.
          History

          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

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