Analysis of the Activities of the Inflammatory Cytokine Macrophage Migration Inhibitory Factor on Activation of Endoplasmic Reticulum Stress Responses

2018 dissertation for MRes. The inflammatory cytokine, Macrophage Migration Inhibitory Factor, was initially isolated in the 1970s as a chemokine involved with inhibition of random movement in Macrophages but has also been linked with many other components of the immune system and even foetal development. It is released almost-ubiquitously, during inflammation, with both pro-inflammatory and anti-inflammatory activities. One key regulator of inflammation is the Unfolded Protein Response. during which the Endoplasmic Reticulum within cells regulates protein flux within the ER lumen, especially when that load is beyond the capacity of the ER to successfully process. As part of the UPR response there is a stop in global translation, enhanced transcription and translation of chaperone proteins, increased ER size and capacity and eventually activation of the apoptosis pathways if the protein load does not reduce to a level within the ER’s capacity. The UPR is controlled via the transduction proteins, IRE1, PERK and ATF6. Because of the UPR’s effect on cellular health and known links to inflammation it was decided to investigate the effects of MIF on UPR activation within cells. Using two different reporter constructs (ATF4.EYFP-N1 or XBP-1.EeYFP-N1) which monitor activation IRE1 and PERK the effects of MIF on UPR activation in HeLa and SH-SY5Y cells was assessed. The observed results show that MIF exerts a marginal suppressive effect on both the IRE1 and PERK between with some variation in the effects of MIF on epithelial (HeLa) or neuronal (SH-SY5Y) origins. This data suggests that MIF may reduce the activation of apoptotic responses within these cells via activation UPR and the PERK pathway through suppression of JNK activity via the noncanonical MIF receptor JAB1. Modulation of UPR responses by MIF would have important downstream effects on the development of auto-inflammatory conditions and neuropathies include Alzheimer’s disease due to the suppressed UPRs inability to resolve the pathological protein load.