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Title: Function and regulation of Fizz1 and Ym1 in Th2 inflammation
Author: Gallagher, I. J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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The elucidation of the macrophage activation pathways stimulated by the innate recognition of bacterial products and the T helper 1 (Th1) cytokine IFN-γ which lead to a proinflammatory or “classically activated” macrophage phenotype is well underway. However macrophages can also be activated by Th2 cytokines such as IL-4 and IL-13, by Fc receptor ligation and by hormonal influences such as glucocorticoids. Macrophage exposure to IL-4 and / or IL-13 leads to “alternative activation” and alternatively activated macrophages have been implicated in the response against helminth parasites and in wound healing. We have developed a model system for generating alternatively activated macrophages in vivo. Implant of the filarial nematode Brugia malayi into the peritoneal cavity of mice gives rise to a cellular response dominated by macrophages with a profoundly Th2 dependent phenotype. These nematode elicited macrophages (NeMΦ) are potent suppressors of cellular proliferations and express the enzyme Arginasel, a marker of alternative activation as well as two further markers of alternative macrophage activation, Ym1 and Fizz1. We investigated the kinetics of the NeMΦ phenotype and found that whilst late expression of Arginasel Fizz1 and Ym1 was a driven by an adaptive Th2 response these genes were also expressed at the earliest timepoints after implant indicating that they had a role in the response to the surgical procedure used to implant B. malayi. The early, injury associated expression of Arginasel mRNA we found to be dependent on IL-4 whilst Fizz1 and Ym1 mRNA expression in this context was dependent on IL-13 signalling through the IL-4Rα. We also found that Fizz1 and Ym1 expression were confined to the lung stage of infection with the gastrointestinal nematode Nippostrongylus brasiliensis where these genes may play a role in the regenerative response after the parasite migration through this tissue. Finally an examination of the regulation of these genes in a trematode model and found that, surprisingly, Fizz1 and Ym1 expression may also be controlled by IFN-γ perhaps through modulation of IL-13 activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available