Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.664639
Title: Modulation of chemokine function during inflammation
Author: Barker, Catriona
ISNI:       0000 0004 5364 597X
Awarding Body: University of Newcastle upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2014
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Abstract:
Oxidative stress is a key feature of inflammatory diseases. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated by many cell types during inflammation. ROS are known to induce chemokines, however it is increasingly apparent that RNS also impact on inflammation. This study was designed to investigate the effects of tissue stress on both chemokine production and function. How stress alters chemokine production in epithelium was established by qPCR. A distinct tissue, stress and chemokine specific response was elicited; of those studied, CXCL8 showed the greatest induction. The chemokines produced by epithelial cells were functional but post-translational modification occurred and so these chemokines may not have their predicted function. The effects of stress in vivo were also assessed. Immunohistochemistry showed association between RNS activity and ischaemic time in a model of kidney ischaemia-reperfusion injury. These observations were extended to human inflammatory liver disease, with increased RNS activity at sites of inflammation, a situation in which chemokines such as CCL2 are also present. RNS also modulates inflammation by post-translational modification. CCL2 was nitrated by RNS creating a chemokine, nCCL2, with decreased chemotactic activity in a diffusion gradient. Similar results were seen for nCCL5 and nCXCL8. Recruitment of HEK-CCR2b cells was decreased following CCL2 nitration and radio-ligand binding experiments confirmed there was some loss of receptor binding. However, the biological significance of this was uncertain. Glycosaminoglycan interactions were prevented by CCL2 nitration as was proportion of transendothelial migration. The ability of nitration to decrease the chemotactic potential of CCL2 was confirmed by in vivo assays. These data show the complexities of the chemokine system. Increased chemokine production by oxidative stress and concurrent modification of those chemokines by RNS represents a powerful paradigm for the regulation of inflammation.
Supervisor: Not available Sponsor: MRC ; NIHR Biomedical Research Centre for Ageing and Age-Related Disease
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.664639  DOI: Not available
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