Date of Graduation

Spring 2010

Degree

Master of Science in Biology

Department

Biology

Committee Chair

Brian Weaver

Abstract

Macrophages play an important role in the sensing of microbial infection and initiating innate immune responses. The activation of macrophages by pro-inflammatory stimuli, such as bacterial LPS, is mediated through changes in the expression of genes that function to promote inflammation. Pro-inflammatory signaling and gene expression is tightly regulated through the parallel induction of anti-inflammatory genes in response to the host cytokine Interleukin-10 (IL-10). The mechanisms by which IL-10 acts to restrain pro-inflammatory signaling remain incompletely defined. Previously, we identified ABIN-3 as an IL-10-inducible gene capable of inhibiting the action of the pro-inflammatory transcription factor NF-κB in human macrophages. Interestingly, IL-10 can induce expression of ABIN-3 only in macrophages concurrently responding to LPS. Herein, I present studies into the mechanism by which IL-10 synergizes with LPS to induce ABIN-3 gene expression. ABIN-3 falls into the category of a secondary response gene requiring new protein synthesis for its induction in response to IL-10 and LPS. I examined whether the induction of ABIN-3 expression is regulated at the level of transcription or at a post-transcriptional level involving an increase in its mRNA stability. These data indicate that IL-10 synergizes with LPS to induce ABIN-3 gene transcription as opposed to inducing stabilization of its mRNA. Future studies will aim to determine the minimal cis-acting elements within the ABIN-3 gene responsible for its induction by both IL-10 and LPS. These studies should ultimately lead to a better understanding of the crosstalk mechanisms between anti- and pro-inflammatory signaling pathways.

Keywords

innate immunity, inflammation, IL-10, LPS, ABIN-3

Subject Categories

Biology

Copyright

© Brian A. Peterson

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