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Scientific article
English

Glatiramer acetate triggers PI3Kdelta/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

Publication date2010
Abstract

Glatiramer acetate (GA), an immunomodulator used in multiple sclerosis (MS) therapy, induces the production of secreted IL-1 receptor antagonist (sIL-1Ra), a natural inhibitor of IL-1beta, in human monocytes, and in turn enhances sIL-1Ra circulating levels in MS patients. GA is a mixture of peptides with random Glu, Lys, Ala, and Tyr sequences of high polarity and hydrophilic nature that is unlikely to cross the blood-brain barrier. In contrast, sIL-1Ra crosses the blood-brain barrier and, in turn, may mediate GA anti-inflammatory activities within the CNS by counteracting IL-1beta activities. Here we identify intracellular signaling pathways induced by GA that control sIL-1Ra expression in human monocytes. By using kinase knockdown and specific inhibitors, we demonstrate that GA induces sIL-1Ra production via the activation of PI3Kdelta, Akt, MEK1/2, and ERK1/2, demonstrating that both PI3Kdelta/Akt and MEK/ERK pathways rule sIL-1Ra expression in human monocytes. The pathways act in parallel upstream glycogen synthase kinase-3alpha/beta (GSK3alpha/beta), the knockdown of which enhances sIL-1Ra production. Together, our findings demonstrate the existence of signal transduction triggered by GA, further highlighting the mechanisms of action of this drug in MS.

Keywords
  • Blotting, Western
  • Gene Knockdown Techniques
  • Glycogen Synthase Kinase 3/genetics/metabolism
  • Humans
  • Interleukin 1 Receptor Antagonist Protein/immunology/*metabolism
  • Mitogen-Activated Protein Kinase Kinases/metabolism
  • Monocytes/immunology
  • Multiple Sclerosis/*drug therapy/*immunology
  • Peptides/*pharmacology
  • Phosphatidylinositol 3-Kinases/metabolism
  • Proto-Oncogene Proteins c-akt/metabolism
  • Signal Transduction/*drug effects/immunology
Citation (ISO format)
CARPINTERO, Rakel et al. Glatiramer acetate triggers PI3Kdelta/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes. In: Proceedings of the National Academy of Sciences of the United States of America, 2010, vol. 107, n° 41, p. 17692–17697. doi: 10.1073/pnas.1009443107
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ISSN of the journal0027-8424
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