Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.542153
Title: Interferon Regulatory Factor 5 (IRF5) : an important player in macrophage polarization and TNF regulation
Author: Krausgruber, Thomas
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Abstract:
Macrophages are dynamic and heterogeneous cells that can be divided into specific, phenotypic subsets. Based on Th1/Th2 polarization concept they are referred to as proinflammatory classical M1 (IL-12high, IL-23high, IL-10low) macrophages and anti-inflammatory M2 (IL-12low, IL-23low, IL-10high) macrophages. In contrast to T lymphocyte subsets, the transcription factor(s) underlying macrophage polarization remain largely unknown. My research has highlighted the importance of Interferon regulatory factor 5 (IRF5) for establishing the pro-inflammatory M1 macrophage phenotype. I was able to show that high expression of IRF5 is characteristic of M1 macrophages, in which it transcriptionally regulates M1-specific cytokines, chemokines and co-stimulatory molecules. Consequently, the depletion of IRF5 in human M1 macrophages results in down-regulation of M1-specific cytokines and further evidence for a role of IRF5 in effective immunity stems from my work using an in vivo model of polarizing inflammation. IRF5 deficient mice showed a significant reduction in serum levels of M1-specific cytokines compared to wild-type littermate controls. Therefore, the suppression of macrophage function via inhibition of IRF5 provides a new approach to attenuate the inflammatory response. Tumor necrosis factor (TNF) plays an essential role in the host defence against infections but is a major factor in the pathogenesis of chronic inflammatory diseases. The expression of TNF is therefore tightly regulated. I was able to demonstrate that IRF5 is not only involved in the induction of human TNF gene expression but also crucial for the late phase secretion of TNF by human myeloid cells. IRF5 is using a complex molecular mechanism to control the TNF gene with two spatially separated regulatory regions (5‟ upstream and 3‟ downstream of the gene) and two independent modes of action (direct DNA binding and formation of IRF5/RelA complex) being involved. The manipulation of the IRF5/RelA interaction could be a putative target for cell-specific modulation of TNF gene expression.
Supervisor: Udalova, Irina ; Dean, Jonathan Sponsor: Arthritis Research UK ; Medical Research Council ; European Community Seventh Framework Programme ; Kennedy Institute Trustees
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.542153  DOI: Not available
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