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Glatiramer acetate triggers PI3K?/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-1?, 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-1? 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 PI3K?, Akt, MEK1/2, and ERK1/2, demonstrating that both PI3K?/Akt and MEK/ERK pathways rule sIL-1Ra expression in human monocytes. The pathways act in parallel upstream glycogen synthase kinase-3?/? (GSK3?/?), 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.

SUBMITTER: Carpintero R

PROVIDER: S-EPMC2955124 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes.

Carpintero Rakel R Brandt Karim J KJ Gruaz Lyssia L Molnarfi Nicolas N Lalive Patrice H PH Burger Danielle D

Proceedings of the National Academy of Sciences of the United States of America 20100927 41

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, ...[more]

PMID: 20876102

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Glatiramer acetate triggers PI3K?/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes.

Publications

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes.

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