Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules acting as post-transcriptional regulators of gene expression. They are involved in many biological processes, and their dysregulation is implicated in various diseases, including multiple sclerosis (MS). Interferon-beta (IFN-beta) is widely used as a first-line immunomodulatory treatment of MS patients. Here, we present the first longitudinal study on the miRNA expression changes in response to IFN-beta therapy. Peripheral blood mononuclear cells (PBMC) were obtained before treatment initiation as well as after two days, four days, and one month, from patients with clinically isolated syndrome (CIS) and patients with relapsing-remitting MS (RRMS). We measured the expression of 651 mature miRNAs and about 19,000 mRNAs in parallel using real-time PCR arrays and Affymetrix microarrays. We observed that the up-regulation of IFN-beta-responsive genes is accompanied by a down-regulation of several miRNAs, including members of the mir-29 family. These differentially expressed miRNAs were found to be associated with apoptotic processes and IFN feedback loops. A network of miRNA-mRNA target interactions was constructed by integrating the information from different databases. Our results suggest that miRNA-mediated regulation plays an important role in the mechanisms of action of IFN-beta, not only in the treatment of MS but also in normal immune responses. miRNA expression levels in the blood may serve as a biomarker of the biological effects of IFN-beta therapy that may predict individual disease activity and progression.
Highlights
Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS), which is characterized by multiple discrete areas of inflammatory demyelination, axonal degeneration, and glial scarring
Many type I IFN-responsive genes harbor in their promoter region a specific sequence motif, the IFN-stimulated response element (ISRE), which is bound by IFN-activated transcription factors (TF) [7]
This suggests that the regulation of miRNAs contributes to the molecular mechanisms of action of IFN-beta in protective immune responses as well as in MS therapy
Summary
Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS), which is characterized by multiple discrete areas of inflammatory demyelination, axonal degeneration, and glial scarring. IFN-beta has broad effects on the gene regulation of blood cells [7,8,9,10,11] This has been shown by several studies that used microarray technology to analyze the gene expression dynamics in the peripheral blood of MS patients in response to IFN-beta therapy. Pedersen et al studied the regulation of miRNAs in Huh cells and primary hepatocytes, which were stimulated with different concentrations of IFN-beta for up to 48 h [28] They observed increased and reduced miRNA expression in response to IFN-beta, and showed that some of the IFN-beta-induced miRNAs mediate antiviral effects against hepatitis C virus.
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