IFNβ and glatiramer acetate trigger different signaling pathways to regulate the IL-1 system in multiple sclerosis
- PMID: 21509198
- PMCID: PMC3073290
- DOI: 10.4161/cib.4.1.14205
IFNβ and glatiramer acetate trigger different signaling pathways to regulate the IL-1 system in multiple sclerosis
Abstract
Imbalance in cytokine homeostasis plays an important part in the pathogenesis of various chronic inflammatory diseases. In multiple sclerosis (MS), the pro-inflammatory cytokine interleukin-1β (IL-1β) is present in the central nervous system, being expressed mainly in infiltrating macrophages and microglial cells. IL-1β activity is inhibited by the secreted form of IL-1 receptor antagonist (sIL-1Ra) whose production is increased in patients' blood and induced in human monocytes by IFNβ and glatiramer acetate (GA)-both immunomodulators displaying similar therapeutic efficacy in MS. Because intracellular pathways are currently considered as potential therapeutic targets, identification of specific kinases used by both immunomodulators might lead to more specific therapeutic targeting. We addressed the question of intracellular pathways used by IFNβ and GA to induce sIL-1Ra in human monocytes in two recent studies. This addendum to these studies aims at discussing common pathways and different elements used by IFNβ and GA to induce sIL-1Ra in human monocytes. This pinpoints PI3Kδ activation as a requirement to induce sIL-1Ra production downstream monocyte stimulation by either IFNβ or GA. However, the immunomodulators differentially use MEK/ERK pathway to induce sIL-1Ra production in human monocytes. Together, our current studies suggest that PI3Kδ and MEK2 might represent new targets in MS therapy.
Keywords: MEK/ERK; PI3K; immunomodulator; inflammation; signal transduction.
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Comment on
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Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes.Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17692-7. doi: 10.1073/pnas.1009443107. Epub 2010 Sep 27. Proc Natl Acad Sci U S A. 2010. PMID: 20876102 Free PMC article.
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A novel MEK2/PI3Kδ pathway controls the expression of IL-1 receptor antagonist in IFN-β-activated human monocytes.J Leukoc Biol. 2010 Dec;88(6):1191-200. doi: 10.1189/jlb.0510312. Epub 2010 Sep 13. J Leukoc Biol. 2010. PMID: 20837746
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