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. 2011 Jan;4(1):112-4.
doi: 10.4161/cib.4.1.14205.

IFNβ and glatiramer acetate trigger different signaling pathways to regulate the IL-1 system in multiple sclerosis

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IFNβ and glatiramer acetate trigger different signaling pathways to regulate the IL-1 system in multiple sclerosis

Rakel Carpintero et al. Commun Integr Biol. 2011 Jan.

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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Figures

Figure 1
Figure 1
Models of how IFNβ and GA activate PI3Kδ/Akt and MEK/ERK pathways to induce sIL-1Ra production in monocytes. (A) IFNβ binds its specific receptor (IFNAR1-IFNAR2), which induces the activation of MEK2 and the translocation of MEK2 and PI3Kδ to the membrane. The activation of PI3Kδ/Akt pathway leads to sIL-1Ra production in monocytes; Grey kinases and proteins are activated but not implicated in sIL-1Ra production. The type 1IFN canonical STAT1 pathway also is dispensable to sIL-1Ra production. (B) GA is recognized by a receptor (cell surface) or a sensor (inside the cell) that transduces signal via activation of both PI3Kδ/Akt and MEK1/2/ERK1/2 pathways. The two pathways then converge to phosphorylate/inactivate GSK3, resulting in the induction of sIL-1Ra production. This scheme is adapted from reference .

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References

    1. Burger D, Dayer JM, Palmer G, Gabay C. Is IL-1 a good therapeutic target in the treatment of arthritis? Best Pract Res Clin Rheumatol. 2006;20:879–896. - PubMed
    1. Arend WP, Palmer G, Gabay C. IL-1, IL-18 and IL-33 families of cytokines. Immunol Rev. 2008;223:20–38. - PubMed
    1. Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, Royen-Kerkhoff A, et al. An autoinflammatory disease with deficiency of the inter-leukin-1-receptor antagonist. N Engl J Med. 2009;360:2426–2437. - PMC - PubMed
    1. Cannella B, Raine CS. The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol. 1995;37:424–435. - PubMed
    1. Mikol DD, Barkhof F, Chang P, Coyle PK, Jeffery DR, Schwid SR, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs. Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7:903–914. - PubMed

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