title: 27-hydroxycholesterol induces production of tumor necrosis factor-alpha from macrophages.
abstract: Enhanced production of TNF-α from macrophages promotes development and instability of atherosclerotic plaques, but involvement of lipid component in TNF-α production has not been clarified in atherosclerosis. We attempted to determine whether cholesterol oxidation products (oxysterols) could modify TNF-α production. Treatment of THP-1 cells with 27-hydroxycholesterol (27OHChol) or 7α-hydroxycholesterol (7αOHChol) resulted in a profound increase in TNF-α transcription, while treatment with an identical concentration of cholesterol and 7-ketochoelsterol did not lead to any change in TNF-α expression. Treatment with 27OHChol resulted in increased synthesis, as well as secretion, of TNF-α, while 7αOHChol led to increased synthesis of TNF-α without affecting secretion of the cytokine. Co-treatment with 7αOHChol or 27OHChol and LPS resulted in synergistically enhanced or augmented secretion of TNF-α. Treatment with TO-901317, pertussis toxin, PP2, and LY294002 resulted not only in attenuated transcription of TNF-α induced by 27OHChol and 7αOHChol, but also secretion of TNF-α enhanced by 27OHChol. This is the first report demonstrating enhanced production of TNF-α in macrophages by treatment with oxysterols which are detected in abundance in atheromatous lesions; in addition, results of the current study provide evidence indicating that certain types of oxysterols contribute to development of atherosclerosis by promoting production of proinflammatory cytokines.
authors.affiliation: Department of Pharmacology, Pusan National University - School of Medicine, Yangsan 626-870, Republic of Korea.
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Kim
authors.forename: Hyojung
authors.initials: H
authors.lastname: Jang
authors.forename: Yonghae
authors.initials: Y
authors.lastname: Son
authors.forename: Sae-A
authors.initials: SA
authors.lastname: Lee
authors.forename: Sun-Sik
authors.initials: SS
authors.lastname: Bae
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Park
authors.forename: Seong-Kug
authors.initials: SK
authors.lastname: Eo
authors.forename: Koanhoi
authors.initials: K
authors.lastname: Kim
mesh_terms: D000818:Animals; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D006888:Hydroxycholesterols / Q000378:metabolism* / Q000494:pharmacology; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D057093:Orphan Nuclear Receptors / Q000819:agonists; D037342:Pertussis Toxin / Q000494:pharmacology; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D002867:Chromones; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D009025:Morpholines; D057093:Orphan Nuclear Receptors; D037342:Pertussis Toxin; D011743:Pyrimidines; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C412373:AG 1879; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C076996:27-hydroxycholesterol