Abstract/Details

Notch-1 regulates IFN-γ secretion through activation of NF-κB


2004 2004

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Abstract (summary)

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.

Indexing (details)


Subject
Immunology
Classification
0982: Immunology
Identifier / keyword
Health and environmental sciences; IFN-gamma; NF-kappaB; Notch-1; T lymphocytes
Title
Notch-1 regulates IFN-γ secretion through activation of NF-κB
Author
Gottipati, Sridevi
Number of pages
109
Publication year
2004
Degree date
2004
School code
0118
Source
DAI-B 65/06, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
Advisor
Osborne, Barbara A.
University/institution
University of Massachusetts Amherst
University location
United States -- Massachusetts
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3136730
ProQuest document ID
305176251
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/305176251
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