A novel MEK2/PI3Kδ pathway controls the expression of IL-1 receptor antagonist in IFN-β-activated human monocytes.
IFN-β and sIL-1Ra play crucial roles in the regulation of innate immunity and inflammation. IFN-β, 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 PI3Kδ and MEK2 as key elements that control sIL-1Ra production in isolated human monocytes activated by IFN-β. Blockade of MEK2, but not of MEK1, by inhibitors and siRNA prevented IFN-β-induced PI3Kδ recruitment to the membrane, Akt phosphorylation, and sIL-1Ra production, suggesting that MEK2 acted upstream of PI3Kδ. Furthermore, ERK1/2, the only identified substrates of MEK1/2 to date, are dispensable for sIL-1Ra production in response to IFN-β stimulation. Upon IFN-β activation, MEK2 and PI3Kδ are translocated to monocyte membranes. These data suggest that MEK1 and MEK2 display different, nonredundant functions in IFN-β 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-β triggers an atypical MEK2/PI3Kδ 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-1β in human monocytes provides a rationale for an alternative, IFN-β-mediated pathway to induce/enhance sIL-1Ra production and thus, to dampen inflammation.
Brandt
Karim J
KJ
Division of Immunology and Allergy, Inflammation and Allergy Research Group, Hans Wilsdorf Laboratory, Department of Internal Medicine, University Hospital and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Carpintero
Rakel
R
Gruaz
Lyssia
L
Molnarfi
Nicolas
N
Burger
Danielle
D
D058534:Class I Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis*; D048369:MAP Kinase Kinase 1 / Q000502:physiology; D048370:MAP Kinase Kinase 2 / Q000502:physiology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D058534:Class I Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D016899:Interferon-beta; D053590:Interleukin 1 Receptor Antagonist Protein; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C482128:MAP2K2 protein, human; C421683:Pik3cd protein, mouse; C482125:MAP2K1 protein, human