title: Mitoxantrone repression of astrocyte activation: relevance to multiple sclerosis.
abstract: Mitoxantrone has been approved by the FDA for the treatment of multiple sclerosis (MS). However, the mechanisms by which mitoxantrone modulates MS are largely unknown. Activated astrocytes produce nitric oxide (NO), TNF-α, and IL-1β, molecules which can be toxic to central nervous system (CNS) cells including oligodendrocytes, thus potentially contributing to the pathology associated with MS. MCP-1 is a chemokine believed to modulate the migration of monocytes to inflammatory lesions present in the CNS of MS patients. IL-12 and IL-23 have been demonstrated to play critical roles in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, by contributing to the development of CD4(+) T cell lineages termed Th1 and Th17, respectively. The current study demonstrates that mitoxantrone inhibits lipopolysachharide (LPS) induction of NO, TNF-α, IL-1β, and MCP-1 production by primary astrocytes. Mitoxantrone also inhibited IL-12 and IL-23 production by these cells. Furthermore, mitoxantrone suppressed the expression of C-reactive protein (CRP). Finally, we demonstrate that mitoxantrone suppressed LPS induction of NF-κB DNA-binding activity, suggesting a novel mechanism by which mitoxantrone suppresses the expression of proinflammatory molecules. Collectively, these studies demonstrate that mitoxantrone represses astrocyte production of potentially cytotoxic molecules, as well as molecules capable of altering T-cell phenotype. These in vitro studies suggest mechanisms by which mitoxantrone may modulate inflammatory diseases including MS.
authors.affiliation: Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 846, Little Rock, AR 72205, United States.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Burns
authors.forename: R
authors.initials: R
authors.lastname: Lee Archer
authors.forename: Janet A
authors.initials: JA
authors.lastname: Chavis
authors.forename: Cameron A
authors.initials: CA
authors.lastname: Tull
authors.forename: Lori L
authors.initials: LL
authors.lastname: Hensley
authors.forename: Paul D
authors.initials: PD
authors.lastname: Drew
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008942:Mitoxantrone / Q000494:pharmacology*; D009103:Multiple Sclerosis
chemical_list: D000893:Anti-Inflammatory Agents; D008942:Mitoxantrone