Date on Master's Thesis/Doctoral Dissertation
Microbiology and Immunology
Microbiology and Immunology, PhD
We identified and characterized a novel defect in β-catenin expression in bone marrow derived dendritic cells (BMDC) from NOD mice, a model for human Type I diabetes. This protein is expressed at high levels throughout the lifespan of the mouse and correlates with increased pro-inflammatory cytokine production by the BMDC and IFNγ induction by T cells cocultured with the BMDC. These defects, including a similar pattern of pro-inflammatory cytokine production, are also observed in human monocytederived DC from diabetic patients. After exploring several potential mechanisms involved in the accumulation of β-catenin in NOD BMDC, we found that β-catenin is phosphorylated at higher levels in NOD BMDC at two residues associated with increased stabilization of this protein. Upon inhibition of the two kinases responsible for these phosphorylations, Akt and PKA, β-catenin expression is reduced. Therefore, β-catenin accumulates in NOD BMDC through an Akt and PKA-mediated mechanism. We also explored mechanisms by which β-catenin influences pro-inflammatory cytokine production and found that inhibition of β-catenin leads to decreased activation of the transcription factor NFκB, suggesting that pro-inflammatory cytokine production is increased in NOD BMDC through an NFκB-dependent mechanism. Finally, we performed several in vivo experiments aimed at inhibiting β-catenin activity or reducing β-catenin expression to reduce disease incidence and/or increase survival. Treatment of NOD mice with quercetin, a β-catenin inhibitor, led to reduced disease incidence and a decreased inflammatory environment. Transfer of β-catenin siRNA-treated BMDC into NOD mice also reduced disease incidence. These studies reveal that β-catenin plays a role in the inflammation leading to diabetes development.
Zirnheld, Arin Lee, "The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development." (2013). Electronic Theses and Dissertations. Paper 2266.