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Notch-1 regulates IFN-gamma secretion through activation of NF-kappaB

by Gottipati, Sridevi

Abstract (Summary)
The cytokine IFN-�³ 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-�³ (IFN-�³) through nuclear factor-�ºB (NF-�ºB) 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 kB�± (I�ºB�±), increased NF-�ºB DNA binding activity, and subsequent IFN-�³ secretion. Inhibiting Notch-1 or NF-�ºB activation abrogated IFN-�³ secretion, indicating that Notch-1 plays an important role in modulating IFN-�³ secretion through NF-�ºB. 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-�ºB activation, and IFN-�³ 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-�ºB activation and IFN-�³ secretion. These data suggest that Notch may modulate peripheral immune responses by regulating IFN-�³ secretion.
Bibliographical Information:

Advisor:

School:University of Massachusetts Amherst

School Location:USA - Massachusetts

Source Type:Master's Thesis

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ISBN:

Date of Publication:01/01/2004

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