Jagged1 regulates the activation of astrocytes via modulation of NFkappaB and JAK/STAT/SOCS pathways

• Published in: Glia Vol. 57; no. 16; p. 1741
• Main Authors: Morga, Eleonora, Mouad-Amazzal, Laila, Felten, Paul, Heurtaux, Tony, Moro, Mike, Michelucci, Alessandro, Gabel, Sebastien, Grandbarbe, Luc, Heuschling, Paul
• Format: Journal Article
• Language: English
• Published: United States 01.12.2009
• Subjects: Animals; Astrocytes - drug effects; Astrocytes - metabolism; Basic Helix-Loop-Helix Transcription Factors - metabolism; Blotting, Western; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cells, Cultured; Cytokines - metabolism; Enzyme-Linked Immunosorbent Assay; Gene Silencing; Gliosis - metabolism; Homeodomain Proteins - metabolism; Inflammation - metabolism; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Jagged-1 Protein; Janus Kinases - metabolism; Lipopolysaccharides - metabolism; Lipopolysaccharides - toxicity; Membrane Proteins - genetics; Membrane Proteins - metabolism; NF-kappa B - metabolism; Nitric Oxide - metabolism; Rats; Rats, Wistar; Receptor, Notch1 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - drug effects; RNA, Messenger - genetics; RNA, Small Interfering - pharmacology; Serrate-Jagged Proteins; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - physiology; STAT1 Transcription Factor - metabolism; Suppressor of Cytokine Signaling Proteins - metabolism; Transcription Factor HES-1; Transfection; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1098-1136
• DOI: 10.1002/glia.20887

The Notch pathway is implicated in many aspects of the central nervous system (CNS) development and functions. Recently, we and others identified the Notch pathway to be involved in inflammatory events of the CNS. To understand the implication of this pathway on astrocytes, we have studied the Jagged-Notch-Hes pathway under inflammatory conditions. LPS exposure induced an upregulation of Jagged1 expression on cultured astrocytes. To address the role of Jagged1 in the modulation of inflammation, we used a siRNA mediated silencing of Jagged1 (siRNA J1). Jagged1 inhibition induced important variations on the Notch pathway components like Hes1, Hes5, Notch3, and RBP-Jkappa. siRNA J1 repressed the mRNA expression of genes known as hallmarks of the gliosis like GFAP and endothelin(B) receptor. On activated astrocytes, the inhibition of Jagged1 had antiinflammatory effects and resulted in a decrease of LPS-induced proinflammatory cytokines (IL1beta, IL1alpha, and TNFalpha) as well as the iNOS expression. The inhibition of Jagged1 induced a modulation of the JAK/STAT/SOCS signaling pathway. Most interestingly, the siRNA J1 decreased the LPS-induced translocation of NFkappaB p65 and this could be correlated to the phosphorylation of IkappaBalpha. These results suggest that during inflammatory and gliotic events of the CNS, Jagged1/Notch signaling sustains the inflammation mainly through NFkappaB and in part through JAK/STAT/SOCS signaling pathways.