Fingolimod induces neuroprotective factors in human astrocytes

Journal of Neuroinflammation

Markus Krumbholz³  Edgar Meinl⁵  Reinhard Hohlfeld¹  Frank Weber²  Verena Loleit⁵  Benno Pütz²  Peter Weber²  Hans Faber²  Sigrid Schwarz⁴  Johannes Melms⁴  Heike Rübsamen⁵  Johann Hofereiter⁵  Franziska S. Hoffmann⁵ 

[1] Munich Cluster for Systems Neurology (SyNergy), Munich, Germany;Max Planck Institute of Psychiatry, Munich, 80804, Germany;Center of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany;German Center for Neurodegenerative Diseases (DZNE) and Technical University, Munich, 81377, Germany;Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich, 81377, Germany

关键词: OAS2;    MX1;    CXCL10/IP10;    B-cell activating factor of the TNF family/TNFSF13b;    Heparin-binding EGF-like growth factor;    Interleukin 11;    Leukemia inhibitory factor;    Neuroprotection;    Astrocyte;    Fingolimod;   

Others  :  1228651
DOI  :  10.1186/s12974-015-0393-6

 received in 2015-03-02, accepted in 2015-09-07,  发布年份 2015

【 摘 要 】

Background

Fingolimod (FTY720) is the first sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of multiple sclerosis. The phosphorylated active metabolite FTY720-phosphate (FTY-P) interferes with lymphocyte trafficking. In addition, it accumulates in the CNS and reduces brain atrophy in multiple sclerosis (MS), and neuroprotective effects are hypothesized.

Methods

Human primary astrocytes as well as human astrocytoma cells were stimulated with FTY-P or S1P. We analyzed gene expression by a genome-wide microarray and validated induced candidate genes by quantitative PCR (qPCR) and ELISA. To identify the S1P-receptor subtypes involved, we applied a membrane-impermeable S1P analog (dihydro-S1P), receptor subtype specific agonists and antagonists, as well as RNAi silencing.

Results

FTY-P induced leukemia inhibitory factor (LIF), interleukin 11 (IL11), and heparin-binding EGF-like growth factor (HBEGF) mRNA, as well as secretion of LIF and IL11 protein. In order to mimic an inflammatory milieu as observed in active MS lesions, we combined FTY-P application with tumor necrosis factor (TNF). In the presence of this key inflammatory cytokine, FTY-P synergistically induced LIF, HBEGF, and IL11 mRNA, as well as secretion of LIF and IL11 protein. TNF itself induced inflammatory, B-cell promoting, and antiviral factors (CXCL10, BAFF, MX1, and OAS2). Their induction was blocked by FTY-P. After continuous exposure of cells to FTY-P or S1P for up to 7 days, the extent of induction of neurotrophic factors and the suppression of TNF-induced inflammatory genes declined but was still detectable. The induction of neurotrophic factors was mediated via surface S1P receptors 1 (S1PR1) and 3 (S1PR3).

Conclusions

We identified effects of FTY-P on astrocytes, namely induction of neurotrophic mediators (LIF, HBEGF, and IL11) and inhibition of TNF-induced inflammatory genes (CXCL10, BAFF, MX1, and OAS2). This supports the view that a part of the effects of fingolimod may be mediated via astrocytes.

【 授权许可】

   
2015 Hoffmann et al.

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