Unraveling natalizumab effects on deregulated miR-17 expression in CD4+ T cells of patients with relapsing-remitting multiple sclerosis

J Immunol Res. 2014;2014:897249. doi: 10.1155/2014/897249. Epub 2014 May 12.

Abstract

MicroRNAs (miRNAs) are a family of noncoding RNAs that play critical roles in the posttranscriptional regulation of gene expression. Accumulating evidence supports their involvement in the pathogenesis of multiple sclerosis (MS). Here, we compare miR-17 expressions in CD4+ T cells from relapsing-remitting (RR) MS patients treated with natalizumab versus untreated patients. miR-17 was downregulated under natalizumab treatment and upregulated during relapse, therefore supporting a possible role of miR-17 in MS immunopathogenesis. Downregulation of miR-17 was associated with upregulation of PTEN, BIM, E2F1, and p21 target genes. In vitro miR-17 inhibition was associated with upregulation of the same targets and resulted in impaired CD4+ T cell activation and proliferation. We further describe deregulated TGFBR2 expression in untreated patients versus healthy volunteers (HVs) and confirm in vitro the link between miR-17 and TGFBR2 expressions. These findings support an effect of natalizumab on expression of specific miRNA and subsequent expression of genes involved in proliferation and control of the cell cycle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology
  • Bcl-2-Like Protein 11
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • Case-Control Studies
  • Cell Cycle / drug effects
  • Cell Migration Inhibition
  • Cell Movement
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / immunology
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / immunology
  • Female
  • Gene Expression Regulation / drug effects*
  • Humans
  • Lymphocyte Activation / drug effects
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • MicroRNAs / genetics*
  • MicroRNAs / immunology
  • Middle Aged
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy*
  • Multiple Sclerosis, Relapsing-Remitting / genetics
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • Multiple Sclerosis, Relapsing-Remitting / pathology
  • Natalizumab
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / immunology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / immunology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / immunology
  • Signal Transduction

Substances

  • Antibodies, Monoclonal, Humanized
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • MIRN17 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • Natalizumab
  • Proto-Oncogene Proteins
  • Receptors, Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • PTEN Phosphohydrolase
  • PTEN protein, human