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Understanding the role of zinc in IL-1β production

Summersgill, Holly

[Thesis]. Manchester, UK: The University of Manchester; 2013.

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Abstract

Zinc is an essential biological trace element required for proper immune functioning. Zinc deficient individuals have been reported to suffer compromised immune responses and increased levels of inflammatory cytokines. Inflammation is integral to the pathology of many disease states, ranging from pathogen dependent infectious disease to non-infectious disease such as cancer, heart disease, diabetes and stroke. One of the main mediators of inflammation is the pro-inflammatory cytokine interleukin-1beta (IL-1beta). Production of IL-1beta occurs via a two step process; firstly the transcription of an inactive pro-form is initiated, followed by protease activation leading to the cleavage of IL-1beta to a mature form. Here it is shown that in vitro zinc depletion of macrophages, using the zinc chelators TPEN and DTPA, leads to pro-IL-1beta cleavage and furthermore to increased release of active IL-1beta. This would suggest that zinc depletion induces activation of proteases that cleave IL-1beta. Caspase-1, ASC, PP2A, cathepsin B and cathepsin G are all shown to regulate zinc depletion-induced IL-1beta release in macrophages. The cell death proteins XIAP and caspase-8 have also been identified to be regulated by zinc depletion in macrophages and there is literature to suggest that these proteins may contribute to IL-1beta processing and release. By identifying a role for zinc depletion in IL-1beta processing we move closer to identifying potential therapeutic targets for zinc deficiency induced inflammatory disease. Zinc also has regulatory roles in the expression of IL-1beta. Here a systems biology approach is utilised to create an explicit representation of the pathways involved in IL-1beta expression. In many in vivo and in vitro models, transcription of pro-Interleukin-1beta is induced by the gram negative cell wall component lipopolysaccharide (LPS). A systematically curated network map of IL-1 transcription has been created. The map encompasses interactions at the macrophage cell membrane, where LPS binds Toll-like receptor 4 (TLR4); the resulting cytoplasmic signalling cascades, including MAPK and NF-kappaB; and finally the specific transcription factor interactions in the nucleus. By creating this model we aim to enable the production of dynamic models of IL-1 transcription.