Regulation of the immunomodulatory cytokine IL-10 by Twist2
Citation:Mirjam W. M. Van den Bosch, 'Regulation of the immunomodulatory cytokine IL-10 by Twist2', [thesis], Trinity College (Dublin, Ireland). School of Biochemistry and Immunology, 2014, pp 252
Van den Bosch TCD THESIS 10518 Regulation of.pdf (PDF) 131.0Mb
Dysregulation of cytokines can lead to infectious and inflammatory diseases. The anti-inflammatory cytokine IL-10 is known to control pro-inflammatory cytokines such as TNF-a, IL-6 and IL-12. The regulation of IL-10 is complex and it has been shown previously that the human tumour suppressor PDCD4 is a negative regulator of IL-10 production. Following LPS stimulation, PDCD4 acts as a molecular switch whereby its degradation results in increased IL-10 production. In this study, I have examined in detail the regulation of PDCD4 in LPS- treated macrophages. I have shown that the mTOR pathway and proteosomal degradation are involved in LPS- induced PDCD4 degradation using rapamycin, an mTOR inhibitor, or the proteosomal inhibitors MG132, both of which block this response. Inhibition of PDCD4 degradation by rapamycin also decreased IL-10 and c-Maf expression, a transcription factor critical for IL-10 induction. I have alson found evidence through immunoprecipitation, of interaction between PDCD4 and Twist2. Through chromatin imunoprecipitation (ChIP) and oligonucleotide pull down assays, I have demonstrated a new regulatory role for PDCD4 and Twist2 in LPS-induced IL10 production by showing increased binding of Twist2 to the c-Maf promoter. The PDCD4-Twist2 complex is inhibitory for LPS-induced c-Maf and IL-10 expression. A new mechanism in the complex regulation of the anti-inflammatory cytokine IL-10 has therefore been discovered.
Author: Van den Bosch, Mirjam W. M.
Qualification name:Doctor of Philosophy (Ph.D.)
Publisher:Trinity College (Dublin, Ireland). School of Biochemistry and Immunology
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Type of material:thesis
Availability:Full text available