Role of tumour necrosis factor receptor subtypes in endothelial cell inflammatory responses

The signalling cascade, produced after THF ligand binding, involves the recruitment of many different signalling proteins, and includes the activation of mitogen-activated protein kinase (MAPK) pathways (e.g. p42/p44 MAPK, p38 MAPK and JNK), as well as the activation of many transcription factors e.g. activating protein-1 (AP-1) and nuclear factor-kB( NF-kB) The aim of this thesis was firstly to investigate the role of TNF-a in the activation of the transcription factor AP-1. Secondly, to investigate TNFR expression in HUVEC cells and then investigates the cellular consequences of TNF treatment on HUVEC cells. Thirdly, we investigated the activation of the MAPK family and the activation of the transcription factors AP-1 and NF­KB in HUVEC cells. Finally, we investigated cell adhesion molecule induction as a result of TNF stimulation in endothelial cells, and then assessed the role of MAPK family members on TNF induced induction of cell surface adhesion molecule expression. Differential activation of TNFRs was also investigated using TNF receptor specific mutant proteins (‘muteins’), to understand the role of either TNFR1 or TNFR2 in these cellular responses. The key finding of this study were that both TNF receptor subtypes were capable of activating AP-1 and NF-kB transcriptional activity in HeLa, HEK 293 or HUVEC cell systems, but to varying degrees. Huvec cells express both TNF receptor subtypes and TNF was found to result in neither death nor proliferation of endothelial cells.EThOS - Electronic Theses Online ServiceGBUnited Kingdo