Molecular analysis of A2A adenosine receptor regulation of NF-kappaB-dependent inflammatory responses

Martin, Anthony F (2004) Molecular analysis of A2A adenosine receptor regulation of NF-kappaB-dependent inflammatory responses. PhD thesis, University of Glasgow.

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Abstract

Adenosine is a potent inhibitor of inflammatory responses, and the A2A adenosine receptor (A2aAR) plays a key role in this process in vivo. This thesis has demonstrated that A2aAR gene expression in human umbilical vein endothelial cells (HUVECs) and in C6 glioma cells could inhibit multiple inflammatory responses in vitro even in the absence of agonist. This is indicated by the reduced induction of the adhesion molecule E-selectin, by over 70% in HUVECs in response to either TNFalpha or LPS isolated from E.coli. In addition, the induction of inducible nitric oxide synthase (iNOS) was abolished in C6 glioma cells following treatment with interferon-gamma (IFNgamma) in combination with LPS or TNFalpha. This suggests that A2aAR expression inhibits a common step in the induction of each of these pro-inflammatory genes. In agreement with this, A2aAR expression was found to inhibit the activity of NF-kB, a key transcription factor in the expression of these pro- inflammatory genes. NF-kB binding to target DNA was severely inhibited in both cell types however, the mechanisms that mediated this were distinct. A2aAR expression in HUVECs inhibited NF-kB translocation to the nucleus independent of any effect on the degradation of IkBalpha. In contrast, receptor expression in C6 glioma cells could block phosphorylation of IkBalpha resulting in its reduced degradation. In addition, receptor expression could also increase IFNgamma-mediated degradation of STATl, which may contribute to the complete loss of iNOS expression. Together, these results indicate that adenosine acting via the A2aAR can inhibit pro-inflammatory responses by specifically inhibiting activation of the NF-kB and JAK-STAT signalling cascades at multiple steps.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Tim Palmer
Keywords: Immunology
Date of Award: 2004
Depositing User: Enlighten Team
Unique ID: glathesis:2004-71144
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 10 May 2019 10:49
URI: http://theses.gla.ac.uk/id/eprint/71144

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