Glatiramer acetate inhibition of tumor necrosis factor-alpha-induced RANTES expression and release from U-251 MG human astrocytic cells.
Glatiramer acetate is an approved drug for the treatment of multiple sclerosis (MS). RANTES is a beta-family chemokine that manifests chemoattractant activity for T lymphocytes and monocytes/macrophages implicated in the pathogenesis of MS lesions. However, the effect of glatiramer acetate on the regulation of RANTES secretion in glial cells is unknown. In the present study, we demonstrate for the first time that treatment of human U-251 MG astrocytic cells with glatiramer acetate blocks tumor necrosis factor-alpha (TNF-alpha)-induced RANTES mRNA and protein in a dose- and time-dependent manner. This effect is attributed to inhibition of transcription and a 40% decrease in transcript stability. Furthermore, our electrophoretic mobility shift assays of nuclear extracts from TNF-alpha-treated cells reveal an increase in DNA-binding activity specific for the nuclear factor-kappa B (NF-kappaB) binding site, in the 5'-flanking promoter region of the human RANTES gene, and that this increase in NF-kappaB binding activity is prevented by pretreatment with glatiramer acetate or the NF-kappaB inhibitors. These findings suggest that glatiramer acetate may exert its therapeutic effect in MS partially through inhibiting NF-kappaB activation and chemokine production.
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Departments of Neurology and Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, USA. qli@hsc.wvu.edu
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Bever
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D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D000068717:Glatiramer Acetate; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D018946:Chemokine CCL5; D018925:Chemokines; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D010455:Peptides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000068717:Glatiramer Acetate