Notch-1 regulates IFN-gamma secretion through activation of NF-kappaB
Abstract (Summary)The cytokine IFN-Ã?Â³ 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-Ã?Â³ (IFN-Ã?Â³) through nuclear factor-Ã?ÂºB (NF-Ã?ÂºB) 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 kBÃ?Â± (IÃ?ÂºBÃ?Â±), increased NF-Ã?ÂºB DNA binding activity, and subsequent IFN-Ã?Â³ secretion. Inhibiting Notch-1 or NF-Ã?ÂºB activation abrogated IFN-Ã?Â³ secretion, indicating that Notch-1 plays an important role in modulating IFN-Ã?Â³ secretion through NF-Ã?ÂºB. Furthermore, using the protein kinase C-[straight theta] (PKC-[straight theta]) inhibitor, rottlerin, as well as peripheral T cells from PKC-knockout (KO) mice, we show that inhibiting PKC-[straight theta] signaling prevents Notch-1 upregulation, NF-Ã?ÂºB activation, and IFN-Ã?Â³ 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-Ã?ÂºB activation and IFN-Ã?Â³ secretion. These data suggest that Notch may modulate peripheral immune responses by regulating IFN-Ã?Â³ secretion.
School Location:USA - Massachusetts
Source Type:Master's Thesis
Date of Publication:01/01/2004