The Mechanism of Caspase-8-Mediated Gene Expression and Its Integral Role in Host Defense / Alexandra Anne DeLaney.

Format:

Book

Thesis/Dissertation

Author/Creator:

DeLaney, Alexandra Anne, author.

Contributor:

Brodsky, Igor E., degree supervisor.

University of Pennsylvania. Department of Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Molecular biology.

Immunology.

Microbiology.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Local Subjects:

Molecular biology.

Immunology.

Microbiology.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Genre:

Academic theses.

Physical Description:

1 online resource (202 pages)

Contained In:

Dissertations Abstracts International 81-04B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2019.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

Caspase-8 is a key integrator of cell survival and cell death decisions during infection and inflammation. Additionally, caspase-8 has an important, but less understood, role in cell-intrinsic inflammatory gene expression. Macrophages lacking caspase-8 have defective inflammatory cytokine expression in response to bacterial infection or TLR stimulation. How caspase-8 regulates cytokine gene expression, and whether caspase-8-mediated gene regulation has a physiological role during infection remains poorly defined. In this thesis we demonstrate that both caspase-8 enzymatic activity and scaffolding functions play a role in control of inflammatory cytokine gene expression. Caspase-8 enzymatic activity mediates IKK phosphorylation and nuclear translocation of the NF-κB family member c-Rel to promote maximal expression of Il1b and Il12b. Overexpression of c-Rel was sufficient to restore expression of IL-12 and IL-1β in caspase-8-deficient cells. Moreover, the cytokine regulatory function of caspase-8 promoted host survival during infection by the intracellular parasite Toxoplasma gondii. Caspase-8-deficient mice displayed acute mortality during T. gondii infection and a defect in intracellular IL-12 production by DCs. Exogenous IL-12 promoted complete survival of caspase-8-deficient mice during acute toxoplasmosis. Our findings provide new insight into how caspase-8 controls inflammatory gene expression and, for the first time, identify a critical role for caspase-8 in host defense against a eukaryotic pathogen.

Notes:

Source: Dissertations Abstracts International, Volume: 81-04, Section: B.

Advisors: Brodsky, Igor E.; Committee members: Mitchell Lazar; Rahul Kohli; Jorge Henao-Mejia; Michael May; Sunny Shin.

Department: Cell and Molecular Biology.

Ph.D. University of Pennsylvania 2019.

Local Notes:

School code: 0175

ISBN:

9781088336755

Access Restriction:

Restricted for use by site license.

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