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.

Production of IL‐27 in multiple sclerosis lesions by astrocytes and myeloid cells: Modulation of local immune responses

“…Moreover, p28 can form a complex with cytokine‐like factor 1 (CLF‐1) (Crabe et al, ); human macrophages under inflammatory conditions have been shown to express CLF‐1 (Kass et al, ). Although human astrocytes can produce the IL‐12p40 subunit (Burns et al, ; Constantinescu et al, ), whether they can also express p35 is not resolved and no data is available pertaining to CLF‐1 production by astrocytes. Therefore, it remains possible that p28 or EBI3, especially in myeloid cells, combines with other partners.…”

Control of autoimmune CNS inflammation by astrocytes

“…In these lines, therapeutic concepts such as the blockade of S1P receptors by FTY720 (34), inhibition of COX2 signaling by analogues of celecoxib (35), increase of cytosolic cGMP by sildenafil (36), as well as other immunomodulatory drugs like resveratrol (37), mitoxantron (38) and dimethylumarate (39) have been demonstrated to inhibit IL-1β production in astrocytes during EAE, the cuprizone induced model of demyelination in vivo as well as LPS induced astrocyte activation in vitro .…”

Multiple Sclerosis: Molecular Mechanisms and Therapeutic Opportunities

“…Some drugs that are approved for therapy of MS, as well as some of those which have shown beneficial effects in clinical or preclinical trials, are known to affect NF-jB-regulated expression and iNOS activity, which may represent an important component of their mechanisms of action. Mitoxantrone (DNA-reactive agent), which is used for the treatment of patients suffering from SPMS, PRMS, or RRMS worsening, is known to suppress NF-jB DNA-binding activity and NO production in stimulated astrocytes (64). Teriflunomide (the inhibitor of pyrimidine de novo synthesis), which is used for oral treatment of patients suffering from RRMS (211), inhibits iNOS in astrocytes (316).…”