title: Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes.
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-1β, 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-1β 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 PI3Kδ, Akt, MEK1/2, and ERK1/2, demonstrating that both PI3Kδ/Akt and MEK/ERK pathways rule sIL-1Ra expression in human monocytes. The pathways act in parallel upstream glycogen synthase kinase-3α/β (GSK3α/β), 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.
authors.affiliation: Division of Immunology and Allergy, Hans Wilsdorf Laboratory, Inflammation and Allergy Research Group, Department of Internal Medicine, University Hospital and Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Rakel
authors.initials: R
authors.lastname: Carpintero
authors.forename: Karim J
authors.initials: KJ
authors.lastname: Brandt
authors.forename: Lyssia
authors.initials: L
authors.lastname: Gruaz
authors.forename: Nicolas
authors.initials: N
authors.lastname: Molnarfi
authors.forename: Patrice H
authors.initials: PH
authors.lastname: Lalive
authors.forename: Danielle
authors.initials: D
authors.lastname: Burger
mesh_terms: D015153:Blotting, Western; D055785:Gene Knockdown Techniques; D000068717:Glatiramer Acetate; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000276:immunology / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009000:Monocytes / Q000276:immunology; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology*; D010455:Peptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D010455:Peptides; D000068717:Glatiramer Acetate; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D020929:Mitogen-Activated Protein Kinase Kinases