Jagged1 regulates the activation of astrocytes via modulation of NFkappaB and JAK/STAT/SOCS pathways.
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.
Morga
Eleonora
E
Laboratoire de Neurobiologie, Life Sciences, Université du Luxembourg, Luxembourg, 1511 Luxembourg. eleonora.morga@uni.lu
Mouad-Amazzal
Laila
L
Felten
Paul
P
Heurtaux
Tony
T
Moro
Mike
M
Michelucci
Alessandro
A
Gabel
Sebastien
S
Grandbarbe
Luc
L
Heuschling
Paul
P
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D020868:Gene Silencing; D005911:Gliosis / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein; D053612:Janus Kinases / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism / Q000633:toxicity; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D051881:Receptor, Notch1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D000072056:Transcription Factor HES-1; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D016207:Cytokines; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D053612:Janus Kinases; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D009569:Nitric Oxide; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D050794:STAT1 Transcription Factor; D000072099:Serrate-Jagged Proteins; D050826:Suppressor of Cytokine Signaling Proteins; D000072056:Transcription Factor HES-1; D014409:Tumor Necrosis Factor-alpha; C489735:Hes1 protein, rat; C000606275:Jag1 protein, rat