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MOLECULAR MECHANISMS OF IL-1 RECEPTOR ACTIVATION
[Thesis]. Manchester, UK: The University of Manchester; 2014.
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Abstract
MOLECULAR MECHANISMS OF IL-1 RECEPTOR ACTIVATIONInterleukin-1 (IL-1) is a pro-inflammatory cytokine that plays an important role in inflammatory responses to injury and infection, both, systemically and within the central nervous system. There are two IL-1 ligands, IL-1α and IL-1β, which bind to the interleukin 1 receptor type I (IL-1RI) activating multiple pathways that lead to the expression of acute phase and pro-inflammatory proteins. Although IL-1α and IL-1β differ in their amino acid sequence (sharing only 26% homology), they are structurally similar (both protein structures are β-barrel comprised of β-sheets), exert their actions through IL-1RI and are thought to exert similar biological activity. However, in recent years, some differences of action have been observed. Briefly, it has been suggested that IL-1β is more potent when acting in the brain, whereas IL-1α has been proposed to be more potent when acting systemically. Despite considerable research efforts, molecular mechanisms responsible for the observed differential effects remain unclear. The aim of this work is to carry out a comparative study of the effects of temperature and pH on the biophysical properties and bioactivities of IL-1α and IL-1β. The thermal stability of both ligands has been investigated using 1D NMR, circular dichroism and fluorescence and all are consistent in that IL-1α and IL-1β retain their folded conformation at increased temperature. Additionally, we found that pH also has a significant influence in their conformation. In this study, we characterized the biophysical properties and bioactivities of IL-1α and IL-1β under different conditions