title: Mitoxantrone exerts both cytotoxic and immunoregulatory effects on activated microglial cells.
abstract: Mitoxantrone (MX) is the most common immunosuppressive drug used in patients with rapidly worsening multiple sclerosis (MS), whose disease is not controlled by β-interferon or glatiramer acetate. Although MX suppresses antigen-presenting cell (APC) and T-cell function in the periphery, its mechanism of action in the central nervous system (CNS) is not known. Given that MX can cross the disrupted blood-brain barrier, such as in MS patients, we in the present study have tested our hypothesis that MX in the CNS exerts cytotoxic and immunomodulatory effects on microglia, the major CNS-resident APCs that play a crucial role in MS pathogenesis. The cytotoxic effect of MX on microglial cells was determined by MTT and flow cytometry test, whereas the regulatory function was tested with enzyme-linked immunosorbent assay (ELISA) method. Indeed, we have found that MX induced microglial cell death in a dose-dependent manner, and the cell death was mainly from late apoptosis and necrosis. Further, MX induced significantly increased levels of interleukin (IL)-10 production of microglia, whereas IL-23p19 production/expression was significantly suppressed. Thus, our study for the first time demonstrates the immunosuppressive/regulatory effect of MX on microglia, which represents an important mechanism underlying the therapeutic effect of this drug on MS patients.
authors.affiliation: Department of Neurology, Union Hospital, Huazhong University of Science & Technology, Wuhan, P.R. China.
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Fei-Li
authors.initials: FL
authors.lastname: Gong
authors.forename: Yuan-Wu
authors.initials: YW
authors.lastname: Mei
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis; D053760:Interleukin-23 Subunit p19 / Q000096:biosynthesis; D051379:Mice; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D008942:Mitoxantrone / Q000494:pharmacology*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; C556062:IL10 protein, mouse; C508841:Il23a protein, mouse; D007166:Immunosuppressive Agents; D053760:Interleukin-23 Subunit p19; D009419:Nerve Tissue Proteins; D016753:Interleukin-10; D008942:Mitoxantrone