Glatiramer acetate blocks interleukin-1-dependent nuclear factor-kappaB activation and RANTES expression in human U-251 MG astroglial cells.
RANTES is a basic 8-kDa polypeptide of the C-C chemokine subfamily with strong chemoattractant activity for T lymphocytes and monocytes/macrophages that are implicated in the pathogenesis of multiple sclerosis (MS) lesions. Glatiramer acetate is a drug recently approved for the treatment of MS. We therefore investigated the effect of glatiramer acetate on RANTES expression in glial cells in vitro. Treatment of human U-251 MG astroglial cells with glatiramer acetate blocks IL-1beta-induced RANTES chemokine production in a dose- and time-dependent manner. Glatiramer acetate also decreased steady-state levels of RANTES mRNA in these cells, which was attributable to reduced transcription, as assessed by nuclear run-on assays. In addition, we showed that NF-kappaB may be the transcriptional activator responsible for the IL-1beta-mediated RANTES gene expression in this system. Our data indicated that the IL-1beta-induced increase in RANTES was associated with an increase in in vitro nuclear extract binding activity specific for the NF-kappaB site in the promoter region of the RANTES gene. The increases in RANTES mRNA and protein expression were suppressed by the NF-kappaB inhibitors gliotoxin, isohelenin, and pyrrolidine dithiocarbamate (PDTC). Furthermore, we demonstrated that the increase in NF-kappaB DNA-binding activity was prevented by pretreatment with glatiramer acetate or the NF-kappaB inhibitors. Our results suggest that glatiramer acetate may inhibit IL-1beta-stimulated RANTES expression in human glial cells by blocking NF-kappaB activation, thus identifying part of the molecular basis for its anti-inflammatory and immunosuppressive effects in demyelinating diseases.
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Departments of Neurology, University of Maryland School of Medicine, 21201, Baltimore, MD, USA. qli001@umaryland.edu
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D001253:Astrocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D001254:Astrocytoma; D001932:Brain Neoplasms; D018946:Chemokine CCL5 / Q000235:genetics* / Q000276:immunology; D020278:Demyelinating Autoimmune Diseases, CNS / Q000188:drug therapy / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D000068717:Glatiramer Acetate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured
D018946:Chemokine CCL5; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D010455:Peptides; D012333:RNA, Messenger; D000068717:Glatiramer Acetate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor