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, 7α-hydroxycholesterol (7αOHChol), 7β-hydroxycholesterol (7βOHChol), 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 7αOHChol and, to a lesser extent, 7K, but not by 7βOHChol. The 7-oxygenated cholesterol derivatives, however, did not change transcription of the IL-8 gene in vascular smooth muscle cells. 7αOHChol-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 7αOHChol, but not with 7K and 7βOHChol, and a specific antagonist of C5a receptor inhibited 7αOHChol-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 7αOHChol. 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 7αOHChol-induced IL-8 expression via PI3K and MEK.
Department of Neurosurgery, Kosin University, College of Medicine, Seo-gu, Busan, Republic of Korea.
Hyok-Rae
HR
Cho
Department of Pharmacology, Pusan National University-School of Medicine, Yangsan, Gyeongnam, Republic of Korea.
Yonghae
Y
Son
Department of Pharmacology, Pusan National University-School of Medicine, Yangsan, Gyeongnam, Republic of Korea.
Sun-Mi
SM
Kim
Department of Pharmacology, Pusan National University-School of Medicine, Yangsan, Gyeongnam, Republic of Korea.
Bo-Young
BY
Kim
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Jeonbuk, Republic of Korea.
Seong-Kug
SK
Eo
Department of Microbiology and Immunology, Pusan National University-School of Medicine, Yangsan, Gyeongnam, Republic of Korea.
Young Chul
YC
Park
Department of Pharmacology, Pusan National University-School of Medicine, Yangsan, Gyeongnam, Republic of Korea.
Koanhoi
K
Kim
D000814:Aniline Compounds / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006888:Hydroxycholesterols / Q000008:administration & dosage / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D007653:Ketocholesterols / Q000008:administration & dosage / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D000814:Aniline Compounds; D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D006888:Hydroxycholesterols; D016209:Interleukin-8; D007653:Ketocholesterols; D020930:MAP Kinase Kinase Kinases; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D044087:Receptor, Anaphylatoxin C5a; D013764:Tetrahydronaphthalenes; C488033:C5AR1 protein, human; C508606:CXCL8 protein, human; C470794:N-((4-dimethylaminophenyl)methyl)-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C011724:cholest-5-en-3 beta,7 alpha-diol; C003001:7-ketocholesterol