Correction to: Leukemia inhibitory factor inhibits erythropoietin-induced myelin gene expression in oligodendrocytes.

An amendment to this paper has been published and can be accessed via the original article.

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

BACKGROUND: The 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. METHODS: Gene 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). RESULTS: In 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. CONCLUSIONS: Cytokines of the gp130 family may have negative effects on myelination, depending on the cytokine environment.

Unwrapping Neurotrophic Cytokines and Histone Modification.

The conventional view that neuroinflammatory lesions contain strictly pro- and anti-inflammatory cytokines is being challenged. Some proinflammatory products e.g. TNF-α are crucial intermediates in axon regeneration, oligodendroglial renewal and remyelination. A more functional system of nomenclature classifies cytokines by their neuro 'protective' or 'suppressive' properties. Beyond the balance of these 'environmental' or 'extrinsic' signals, specific 'intrinsic' determinants of cytokine signalling appear to influence the outcome of axoglial regeneration. In this commentary, we examine the potential importance of cytokine-induced histone modification on oligodendrocyte differentiation. Neuroinflammation mediates the release of astrocytic leukaemia inhibitory factor (LIF) and erythropoietin (EPO) which potentiates oligodendrocyte differentiation and myelin production. Meanwhile, histone deacetylation strongly suppresses important inhibitors of oligodendrocyte differentiation. Given that LIF and EPO induce histone deacetylases in other systems, future studies should examine whether this mechanism significantly influences the outcome of cytokine-induced remyelination, and whether epigenetic drug targets could potentiate the effects of exogenous cytokine therapy.

Erythropoietin Increases Myelination in Oligodendrocytes: Gene Expression Profiling Reveals Early Induction of Genes Involved in Lipid Transport and Metabolism.

Several studies have shown that erythropoietin (EPO) has neuroprotective or neuroreparative actions on diseases of the nervous system and that improves oligodendrocyte (OL) differentiation and myelination in vivo and in vitro. This study aims at investigating the early molecular mechanisms for the pro-myelinating action of EPO at the gene expression level. For this purpose, we used a differentiating OL precursor cell line, rat central glia-4 cells. Cells were differentiated or not, and then treated with EPO for 1 or 20 h. RNA was extracted and changes in the gene expression profile were assessed using microarray analysis. Experiments were performed in biological replicates of n = 4. Differentiation alone changed the expression of 11% of transcripts (2,663 out of 24,272), representing 2,436 genes, half of which were upregulated and half downregulated. At 20 h of treatment, EPO significantly affected the expression of 99 genes that were already regulated by differentiation and of 150 genes that were not influenced by differentiation alone. Analysis of the transcripts most upregulated by EPO identified several genes involved in lipid transport (e.g., Cd36) and lipid metabolism (Ppargc1a/Pgc1alpha, Lpin1, Pnlip, Lpin2, Ppard, Plin2) along with Igf1 and Igf2, growth factors known for their pro-myelinating action. All these genes were only induced by EPO and not by differentiation alone, except for Pnlip which was highly induced by differentiation and augmented by EPO. Results were validated by quantitative PCR. These findings suggest that EPO might increase remyelination by inducing insulin-like growth factors and increasing lipid metabolism.

A case of leprosy in Malawi. Making the final push towards eradication: a clinical and public health perspective.

Statistically speaking, Malawi has achieved the World Health Organisation's target for the elimination of leprosy (<1 case per 10 000 people), yet the disease is still considered a leading cause of long term physical disability. In this case study the authors discuss the presentation of a 39-year-old gentleman to a district hospital in Malawi with multibacillary, lepromatous leprosy. The condition was initially managed in the community as an 'allergy' which suggests that local barriers currently hinder the detection of leprosy in this developing primary care system. Leprosy is a multi-system disease and this gentleman demonstrated evidence of lepromatous orchitis. Promoting an awareness of these systemic manifestations will increase the the detection of complications and circumvent long term morbidity. Efforts to optimise systems of detection, management and public and professional education are essential to drive eradication in these at-risk populations. At an international level, we must strive to fulfil the objectives outlined by the 'Enhanced Global Strategy for Further Reducing the Disease Burden due to Leprosy for 2011-2015'. At a national level, local research should delineate community factors that impede the eradication of leprosy. Developing new diagnostic and epidemiologic tools, more efficacious chemoprophylactic regimens and vaccination for endemic regions would facilitate these efforts.