On the role of 25-hydroxycholesterol synthesis by glioblastoma cell lines. Implications for chemotactic monocyte recruitment

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• 作者：Gerald Eibinger ; G¨¹nter Fauler ; Eva Bernhart ; Sasa Frank ; Astrid Hammer ; Andrea Wintersperger ; Hans Eder ; Akos Heinemann ; Paul S. Mischel ; Ernst Malle ; Wolfgang Sattler
• 关键词：EBI2 ; Migration ; Glioblastoma ; TNF¦Á ; IL1¦Â
• 刊名：Experimental Cell Research
• 出版年：2013
• 出版时间：15 July, 2013
• 年：2013
• 卷：319
• 期：12
• 页码：1828-1838
• 全文大小：2468 K

文摘

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor and is invariably fatal to affected patients. Oxysterols belong to a class of bioactive lipids that are implicated in neurological disease and are associated with various types of cancer. Here, we investigated expression and transcriptional regulation of cholesterol 25-hydroxylase (CH25H) in human U87MG and GM133 glioblastoma cell lines. We demonstrate that in both cell lines transcription and translation of CH25H are increased in response to TNF¦Á and IL1¦Â. In parallel, both cell lines upregulate 25-hydroxycholesterol (25-OHC) synthesis and secretion to levels comparable to bone marrow-derived mouse macrophages under inflammatory conditions. To determine whether 25-OHC acts as chemoattractant for tumor-associated macrophages, the human THP-1 monoblastic leukemia cell line was treated with varying amounts of the oxysterol. Experiments revealed that 25-OHC and lipid extracts isolated from GM133-conditioned medium (containing 7-fold higher 25-OHC concentrations than U87MG medium) induce chemotactic migration of THP-1 cells. Of note, 25-OHC also induced the migration of primary human peripheral blood monocytes. In response to exogenously added 25-OHC, THP-1 cells reorganized intermediate filament-associated vimentin to more cortical and polarized structures. Chemotactic migration of monocytes in response to 25-OHC was pertussis toxin-sensitive, indicating the involvement of G protein-coupled receptors. Using RNA interference we demonstrated that G protein-coupled receptor 183 (EBI2) contributes to 25-OHC-mediated chemotactic migration of THP-1 cells. These in vitro data indicate that GBM-derived and secreted 25-OHC may be involved in the recruitment of immune-competent cells to a tumor via EBI2.