Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Youhai H. Chen

Abstract

TNF-alpha-induced protein 8 (TNFAIP8 or TIPE) is a newly described regulator of cancer and infection. However, its precise roles and mechanisms of actions are not well understood. Here I report the generation of TNFAIP8 knockout mice and describe their increased responsiveness to colonic inflammation and resistance to lethal Listeria monocytogenes infection. TNFAIP8 knockout mice were generated by germ line gene targeting and were born without noticeable developmental abnormalities. Their major organs including those of the immune and digestive systems were macroscopically and microscopically normal. However, compared to wild type mice, TNFAIP8 knockout mice exhibited significant differences in the development of listeriosis and experimentally induced colitis. I discovered that TNFAIP8 regulates L. monocytogenes infection by controlling pathogen invasion and host cell apoptosis potentially in a RAC1 GTPase-dependent manner. TNFAIP8 knockout mice had reduced bacterial load in the liver and spleen and TNFAIP8 knockdown in murine liver HEPA1-6 cells increased apoptosis, reduced bacterial invasion into cells, and resulted in dysregulated RAC1 activation. The combined effect of reduced bacterial invasion and increased sensitivity to TNF-alpha-induced clearance likely protected the TNFAIP8 knockout mice from lethal listeriosis. On the other hand, I also discovered that the increased apoptosis sensitized TNFAIP8 knockout mice to dextran sodium sulfate-induced colitis as demonstrated by decreased survival rates and increased body weight loss of TNFAIP8 knockout mice, and enhanced leukocyte infiltration, bacterial invasion, and inflammatory cytokine production in the TNFAIP8 knockout colon. Bone marrow chimeric experiments revealed that TNFAIP8 deficiency in non-hematopoietic cells was responsible for the exacerbated colitis and resistance to listeriosis in TNFAIP8 knockout mice. Taken together, these findings indicate that TNFAIP8 plays an important role in maintaining colon homeostasis, protecting against colitis, and regulating the pathogenesis of L. monocytogenes infection by controlling bacterial invasion and/or cell death of the non-immune cells.

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