

Other version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955124/pdf/pnas.201009443.pdf
![]() |
Glatiramer acetate triggers PI3Kdelta/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes |
|
Authors | ||
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 | PMID: 20876102 | |
Full text |
![]() ![]() Other version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955124/pdf/pnas.201009443.pdf |
|
Structures | ||
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 |