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Notch-1 regulates IFN-gamma secretion through activation of NF-kappaB
The cytokine IFN-γ is important in mediating immune responses, while the Notch family of transmembrane receptors has been implicated in modulating T cell differentiation at several stages of development. Stimulation of peripheral T cells through the T cell receptor (TCR) increases Notch-1 expression, and here we show that Notch-1 specifically upregulates interferon-γ (IFN-γ) through nuclear factor-κB (NF-κB) activation. Overexpressing the active form of Notch-1 in T cell lines or upregulating Notch-1 by TCR stimulation in peripheral T cells leads to phosphorylation of inhibitor of kBα (IκBα), increased NF-κB DNA binding activity, and subsequent IFN-γ secretion. Inhibiting Notch-1 or NF-κB activation abrogated IFN-γ secretion, indicating that Notch-1 plays an important role in modulating IFN-γ secretion through NF-κB. Furthermore, using the protein kinase C-&thetas; (PKC-&thetas;) inhibitor, rottlerin, as well as peripheral T cells from PKC-knockout (KO) mice, we show that inhibiting PKC-&thetas; signaling prevents Notch-1 upregulation, NF-κB activation, and IFN-γ production. Additionally, we also show that Notch-1 activates ERK1/2 MAP kinase and that inhibition of ERK1/2 with MAP kinase inhibitor PD98059 prevents Notch-1-upregulated NF-κB activation and IFN-γ secretion. These data suggest that Notch may modulate peripheral immune responses by regulating IFN-γ secretion. ^
Health Sciences, Immunology
"Notch-1 regulates IFN-gamma secretion through activation of NF-kappaB"
(January 1, 2004).
Electronic Doctoral Dissertations for UMass Amherst.