Interleukin-1 is a large family of cytokines and an important mediator of innate immunity. Whilst IL-1 plays an essential role in host defence and resolution of damage, failure in its regulation can result in excessive and harmful inflammation. Numerous anti-IL-1 therapies are already licenced for the treatment of non-communicable diseases such as pancreatic cancer, rheumatoid arthritis and atopic dermatitis. However, our comprehension of biological processes controlling IL-1 is far from complete. This thesis aims to expand our understanding of IL-1 cleavage and secretion from innate immune cells. Firstly, this work describes the requirement for transcriptional and post-translational priming for the production of biologically active IL- 1beta and IL-18 from primary human monocytes. As such, upstream mechanisms that manage the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome: a multi protein complex that mediates caspase-1 dependent cleavage of IL-1beta and IL-18 were investigated. Moreover, the regulation of the anti-inflammatory IL-1 member IL-37 were examined. IL-37 cleavage was found to be constitutive, whilst the release of its processed form was dependent on the canonical NLRP3 inflammasome, lytic cell death and plasma membrane permeability. Post-translational control of IL-1 itself was also explored. IL-1alpha, a pro-inflammatory alarmin, was found to be regulated by phosphorylation, which had an important role in IL-1alpha subcellular localisaton and release. Thus, this thesis made a novel contribution to the IL-1 field by investigating the regulation of both pro- and anti-inflammatory members of this family in response to inflammatory stimuli.
Mechanisms of Regulation of the Interleukin-1 Family in Inflammation
Gritsenko, A. (Author). 1 Aug 2022
Student thesis: Phd