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  • Title: Nuclear factor-kappa β regulates Notch signaling in production of proinflammatory cytokines and nitric oxide in murine BV-2 microglial cells.
    Author: Cao Q, Kaur C, Wu CY, Lu J, Ling EA.
    Journal: Neuroscience; 2011 Sep 29; 192():140-54. PubMed ID: 21729740.
    Abstract:
    Microglial cells exhibit Notch-1 signaling expression which is enhanced upon activation. We reported previously that enhanced Notch-1 expression in activated microglia modulates production of proinflammatory cytokines and nitric oxide (NO). Furthermore, Notch-1 modulates transcription factor nuclear factor-kappa B (NF-κB). This study was aimed to investigate if NF-κB reciprocally modulates Notch signaling in BV-2 cells. In this connection, the cells were pretreated with caffeic acid phenethyl ester (Cape) followed by stimulating the cells with lipopolysaccharide (LPS). Cape+LPS treatment resulted in reduced translocation of NF-κB into the nucleus. Concomitantly, NF-κB DNA binding activity and the mRNA and protein expression levels of NF-κB/p65, Notch-1, intracellular domain of Notch-1 receptor (NICD), Hes-1, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and inducible nitric oxide synthase (iNOS) along with nitrite level were significantly reduced. Additionally, flow cytometry analysis showed a decrease in expression levels of NF-κB/p65, Notch-1, NICD but an increase in that of signal transducers and activators of transcription 3 (Stat3). Furthermore, nuclear Hes-1, phosphorylated Stat3 (p-Stat3) and recombination signal-binding protein 1 for J-Kappa (RBP-JK) expression levels were significantly suppressed. The present results suggest that Cape inhibits NF-κB activation through suppressing its interaction with DNA. Cape-induced reduction of Hes-1 may be attributed to decreased interaction between NICD and RBP-JK whose levels were reduced concurrently. Hes-1 reduction may lead to decreased production of inflammatory cytokines and NO. It is concluded that NF-κB can modulate Notch-1 signaling. Both pathways operate synergistically for production of proinflammatory cytokines and NO in activated microglia.
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