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

Carpintero, Rakel; Brandt, Karim; Gruaz, Lyssia; Molnarfi, Nicolas; Lalive d'Epinay, Patrice; Burger, Danielle

doi:10.1073/pnas.1009443107

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Title		Glatiramer acetate triggers PI3Kdelta/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes
Authors		Carpintero, Rakel Brandt, Karim Gruaz, Lyssia Molnarfi, Nicolas Lalive d'Epinay, Patrice Burger, Danielle
Published in		Proceedings of the National Academy of Sciences of the United States of America. 2010, vol. 107, no. 41, p. 17692-17697
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
Identifiers		DOI: 10.1073/pnas.1009443107 PMID: 20876102
Full text		Article - Limited access to UNIGE Other version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955124/pdf/pnas.201009443.pdf
Structures		Faculté de médecine / Section de médecine clinique / Département de médecine
Research groups		Inflammation et allergie (874) Scléroses en plaques, neuroimmunologie, encéphalite autoimmune expérimentale (843)
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 https://archive-ouverte.unige.ch/unige:20822