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Scientific article
English

A novel MEK2/PI3Kdelta pathway controls the expression of IL-1 receptor antagonist in IFN-beta-activated human monocytes

Published inJournal of leukocyte biology, vol. 88, no. 6, p. 1191-1200
Publication date2010
Abstract

IFN-beta and sIL-1Ra play crucial roles in the regulation of innate immunity and inflammation. IFN-beta, which is widely used to improve the course of relapsing, remitting multiple sclerosis, induces the production of sIL-1Ra in human monocytes through mechanisms that remain largely unknown. In this study, we identified PI3Kdelta and MEK2 as key elements that control sIL-1Ra production in isolated human monocytes activated by IFN-beta. Blockade of MEK2, but not of MEK1, by inhibitors and siRNA prevented IFN-beta-induced PI3Kdelta recruitment to the membrane, Akt phosphorylation, and sIL-1Ra production, suggesting that MEK2 acted upstream of PI3Kdelta. Furthermore, ERK1/2, the only identified substrates of MEK1/2 to date, are dispensable for sIL-1Ra production in response to IFN-beta stimulation. Upon IFN-beta activation, MEK2 and PI3Kdelta are translocated to monocyte membranes. These data suggest that MEK1 and MEK2 display different, nonredundant functions in IFN-beta signaling. That neither MEK1 nor ERK1/2 play a part in this mechanism is also an unexpected finding that gives rise to a better understanding of the MAPK signaling network. Together, these findings demonstrate that IFN-beta triggers an atypical MEK2/PI3Kdelta signaling cascade to regulate sIL-1Ra expression in monocytes. The premise that MEK1 and MEK2 play a part in the induction of the proinflammatory cytokine, IL-1beta in human monocytes provides a rationale for an alternative, IFN-beta-mediated pathway to induce/enhance sIL-1Ra production and thus, to dampen inflammation.

Keywords
  • Extracellular Signal-Regulated MAP Kinases/physiology
  • Humans
  • Interferon-beta/*pharmacology
  • Interleukin 1 Receptor Antagonist Protein/*biosynthesis
  • MAP Kinase Kinase 1/physiology
  • MAP Kinase Kinase 2/*physiology
  • Monocytes/drug effects/*metabolism
  • Phosphatidylinositol 3-Kinases/*physiology
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt/metabolism
  • Signal Transduction/*physiology
Citation (ISO format)
BRANDT, Karim et al. A novel MEK2/PI3Kdelta pathway controls the expression of IL-1 receptor antagonist in IFN-beta-activated human monocytes. In: Journal of leukocyte biology, 2010, vol. 88, n° 6, p. 1191–1200. doi: 10.1189/jlb.0510312
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ISSN of the journal0741-5400
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