Abstract
BackgroundTeriflunomide, an inhibitor of dihydroorotate dehydrogenase, is thought to ameliorate multiple sclerosis by reducing activation-induced proliferation of lymphocytes, which is highly dependent on de novo pyrimidine synthesis. Nevertheless, its immunomodulatory effects on resident glial cells in the central nervous system are only poorly understood.MethodsIn this study, we employed physiologically relevant concentrations of teriflunomide and investigated its effects on survival, proliferation, activation, and function of primary rat microglia in vitro.ResultsWe demonstrate that teriflunomide had no cytotoxic effect on microglia and had only a minor impact on microglial activation. In a concentration- and time-dependent manner, teriflunomide significantly downregulated surface expression of the co-stimulatory molecule CD86. Furthermore, in the highest concentration applied (5 μM), it slightly increased the expression of interleukin-10 in microglia in response to lipopolysaccharide. Treatment with low concentrations of teriflunomide (0.25–1 μM) did not have any impact on the activation or proliferation of microglia. At 5 μM concentration of teriflunomide, we observed a reduction of approximately 30 % in proliferation of microglia in mixed glial cell cultures.ConclusionsTaken together, our in vitro findings suggest that at higher concentrations, teriflunomide potentially exerts its effects by reducing microglial proliferation and not by modulating the M1-/M2-like cell differentiation of primary rat microglia. Thus, teriflunomide has no major impact on the plasticity of microglia; however, the anti-proliferative and minimal anti-inflammatory effects might be clinically relevant for immune modulation in the treatment of neuroinflammatory CNS diseases such as multiple sclerosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0715-3) contains supplementary material, which is available to authorized users.
Highlights
Teriflunomide, an inhibitor of dihydroorotate dehydrogenase, is thought to ameliorate multiple sclerosis by reducing activation-induced proliferation of lymphocytes, which is highly dependent on de novo pyrimidine synthesis
Regulation of dihydroorotate dehydrogenase (DHODH)-messenger RNA (mRNA) expression in microglia Previous reports have revealed that teriflunomide inhibits activation-induced proliferation of T cells by targeting DHODH, which is a crucial enzyme involved in de novo synthesis of pyrimidine nucleotides [1, 2]
Following the stimulation of microglia with LPS/IFN-γ or granulocyte macrophage-colony stimulating factor (GM-CSF), we studied the expression of DHODH-mRNA by reverse transcription polymerase chain reaction (RT-PCR)
Summary
Teriflunomide, an inhibitor of dihydroorotate dehydrogenase, is thought to ameliorate multiple sclerosis by reducing activation-induced proliferation of lymphocytes, which is highly dependent on de novo pyrimidine synthesis. It is thought to act primarily via a specific, noncompetitive, and reversible inhibition of the activity of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which is required for de novo pyrimidine synthesis of rapidly dividing cells such as activated lymphocytes [1, 2]. Wostradowski et al Journal of Neuroinflammation (2016) 13:250 proliferating lymphocytes in the periphery [5, 6] This limits the availability of autoreactive T and B cells that can infiltrate into the central nervous system (CNS) in CNS inflammatory diseases such as multiple sclerosis (MS) [7]. Other effects of teriflunomide such as the inhibition of adhesion molecules, cytokines, protein tyrosine kinases, nuclear factor-kB (NF-kB) activation, and cyclooxygenase 2 activity have been demonstrated in some in vitro studies, suggesting that teriflunomide in addition to its anti-proliferative effects may impact signal transduction, migration, and inflammatory processes [8, 9]
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