Date of Graduation

Summer 2014

Degree

Master of Science in Biology

Department

Biology

Committee Chair

Brian Weaver

Abstract

To mitigate damage to host tissues associated with a prolonged inflammatory state, the cytokine interleukin-10 (IL-10) induces expression of a set of anti-inflammatory genes that act to inhibit expression of TLR-induced pro-inflammatory genes. While many of the IL-10-induced genes can be induced by IL-10 stimulation alone, some others, such as TNIP3, are only IL-10-inducible in the presence of concurrent TLR signaling, and are thus termed IL-10 super-induced genes. TNIP3 is part of a larger cohort of IL-10 super-induced genes, and the synergy for these genes occurs at a transcriptional level, not due to mRNA stabilization. Furthermore, these IL-10 super-induced genes can be subdivided into three distinct kinetic profiles: primary response genes, early-induced secondary response genes, and late-induced secondary response genes. To further understand the regulatory mechanisms in play, I used ChIP and reporter gene assays to confirm the IL-10 super-induction of these genes occurs at the level of transcription, depending on an increase of RNA polymerase II recruitment to the TNIP3 promoter. Additionally, I found that the three-wave kinetic profiles of induction are conserved in both human and mouse macrophages, and that the coordinated and temporal expression of the three gene subsets appears to correlate with differing dependencies on PI3K and JNK signaling pathways.

Keywords

IL-10, toll-like receptor, macrophages, transcriptional control, TNIP3, PI3K, MAPK

Subject Categories

Biology

Copyright

© Amanda Fields Dillow

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