The Differential Activation Of Downstream Unfolded Protein Response Pathways in Human Cell Lines

Abstract

HLA-B27 heavy chain misfolding has been linked to the pathogenesis of the chronic inflammatory disease Ankylosing Spondylitis. Ankylosing Spondylitis is a disease which primarily affects the axial skeleton but has also been shown to affect various other organs including the heart, lungs and eyes. However, there is limited evidence to show how HLA-B27 misfolding leads to differing responses in different cell types. This study sought to investigate the activation of common downstream pathways of the unfolded protein response in HT1080 and HeLa cells in response to tunicamycin in the hope of translating the data into an Ankylosing Spondylitis disease model. The pathways that were investigated were the autophagy, apoptosis and inflammatory signalling pathways.
It was found that in i) HT1080 cells, as a response to immediate induction of ER stress, endoplasmic reticulum membranes expanded to cope with stress but then employed different responses to cope with prolonged ER stress. ii) In both HeLa and HT1080 cells, autophagy was differentially activated, with HT1080 cells and HeLa cells activating autophagy pathways during early and late tunicamycin induced ER stress responses respectively. iii) HT1080 cells did not activate apoptosis during both early and late responses as opposed to HeLa cells, where apoptosis activation was seen in late ER stress responses. And finally iv) HT1080 and HeLa cells were found to have differential tyrosine kinase signalling in both early and late ER stress responses.
The observations that these different cell lines have differing coping mechanisms to ER stress may have implications in elucidating the pathogenesis of AS and in the development of more effective therapies.