Leukemia inhibitory factor inhibits erythropoietin-induced myelin gene expression in oligodendrocytes

Abstract

BackgroundThe pro-myelinating effects of leukemia inhibitory factor (LIF) and other cytokines of the gp130 family, including oncostatin M (OSM) and ciliary neurotrophic factor (CNTF), have long been known, but controversial results have also been reported. We recently overexpressed erythropoietin receptor (EPOR) in rat central glia-4 (CG4) oligodendrocyte progenitor cells (OPCs) to study the mechanisms mediating the pro-myelinating effects of erythropoietin (EPO). In this study, we investigated the effect of co-treatment with EPO and LIF.MethodsGene expression in undifferentiated and differentiating CG4 cells in response to EPO and LIF was analysed by DNA microarrays and by RT-qPCR. Experiments were performed in biological replicates of N ≥ 4. Functional annotation and biological term enrichment was performed using DAVID (Database for Annotation, Visualization and Integrated Discovery). The gene-gene interaction network was visualised using STRING (Search Tool for the Retrieval of Interacting Genes).ResultsIn CG4 cells treated with 10 ng/ml of EPO and 10 ng/ml of LIF, EPO-induced myelin oligodendrocyte glycoprotein (MOG) expression, measured at day 3 of differentiation, was inhibited ≥4-fold (N = 5, P < 0.001). Inhibition of EPO-induced MOG was also observed with OSM and CNTF. Analysis of the gene expression profile of CG4 differentiating cells treated for 20 h with EPO and LIF revealed LIF inhibition of EPO-induced genes involved in lipid transport and metabolism, previously identified as positive regulators of myelination in this system. In addition, among the genes induced by LIF, and not by differentiation or by EPO, the role of suppressor of cytokine signaling 3 (SOCS3) and toll like receptor 2 (TLR2) as negative regulators of myelination was further explored. LIF-induced SOCS3 was associated with MOG inhibition; Pam3, an agonist of TLR2, inhibited EPO-induced MOG expression, suggesting that TLR2 is functional and its activation decreases myelination.ConclusionsCytokines of the gp130 family may have negative effects on myelination, depending on the cytokine environment.Electronic supplementary materialThe online version of this article (10.1186/s10020-018-0052-3) contains supplementary material, which is available to authorized users.

Systemic TLR2 tolerance enhances central nervous system remyelination

“…Furthermore, mice with a global deletion in TLR2 demonstrated enhanced remyelination in vivo after direct CNS administration of lysolecithin to induce demyelination [15], although these studies did not examine cuprizone-induced demyelination. Additional evidence suggesting an inhibitory role for TLR2 signaling in CNS remyelination include a study demonstrating that the TLR2 agonist, P3C, inhibited the pro-myelinating effects of erythropoietin [14], and a study reporting that cuprizone feeding resulted in increased expression of TLR2 in the CC and hippocampus [13]. Based on these prior studies of the potential involvement of TLR2 in the remyelination process, the lack of feasibility of a practical therapeutic approach for deleting TLR2 in vivo, and our EAE study suggesting the potential for a therapeutic reduction in TLR2 signaling using TLR2 tolerance induction [10], the goal in the present study was to test the role of TLR2 tolerance induction in the process of remyelination.…”

Leukemia inhibitory factor: Recent advances and implications in biotechnology

“…This finding demonstrated an unknown aspect of dysregulation in MS [32]. In vitro studies have further substantiated the important role of LIF concentration demonstrating its relation with increased expression of the erythropoietin receptor [33], the ability to enhance astrocytes interaction with oligodendrocytes [28], and how the use of enhancers for LIF secretion may help in the treatment of multiple sclerosis [34].…”

“…The initial response to multiple sclerosis is remyelination, guaranteed by the proliferation and maturation of oligodendrocyte progenitor cells (OPCs) [33,35,36]. Studies with mice restricted to a cuprizone diet demonstrated the central role of LIF in this process, promoting the differentiation of these cells in different brain regions (cerebellum and corpus callosum) [35,36].…”

“…LIF-induced processes are dependent on the cytokine microenvironment and are mediated by the presence of erythropoietin (EPO), which has been found to display neuroprotective J o u r n a l P r e -p r o o f functions and emerged as a possible therapy for neurodegenerative diseases [37]. In vitro studies using OPCs from rats overexpressing EPO receptors, demonstrated the importance of LIF concentration in regulating EPO-induced myelin gene expression in oligodendrocytes (ODs) [33]. In the presence of EPO, high concentrations of LIF (> 10 ng/mL) activate SOCS3, a factor responsible for blocking the EPO receptor, resulting in a decrease of MOG expression and leading to the inhibition of OD maturation (Figure 2B).…”

Leukemia inhibitory factor regulates Schwann cell proliferation and migration and affects peripheral nerve regeneration

“…Our present study demonstrates the benefiting roles of ERFE on Schwann cell proliferation and migration and thus indicates that EPO may encourage peripheral nerve regeneration via producing ERFE. An investigation of the association of LIF and EPO showed that in oligodendrocytes, LIF can inhibit EPO-induced, lipid transport and metabolism-associated genes 36 . Therefore, in Schwann cells, LIF may also negatively regulate EPO-induced ERFE and mediate peripheral nerve regeneration.…”