No abstract

Interleukin-1[beta] (IL-1[beta]) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in wide-spread diseases. Therefore, IL-1[beta] activity must be fine-tuned to enable anti-microbial responses whilst limiting collateral damage. Here we report that precursor IL-1[beta] is rapidly turned over by the proteasome and this correlates with its decoration by K11-, K63- and K48-linked ubiquitin chains. The ubiquitylation of IL-1[beta] is not just a degradation signal triggered by inflammasome priming and activating stimuli, but also limits IL-1[beta] cleavage by caspase-1. We further demonstrate that IL-1[beta] K133 is modified by ubiquitin and forms a salt bridge with IL-1[beta] D129. Loss of IL-1[beta] K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1[beta]. Accordingly, IL-1[beta] K133R/K133R mice display increased precursor IL-1[beta] upon inflammasome priming and increased bioactive IL-1[beta], both in vitro and following LPS injection in vivo. These findings reveal new mechanisms for limiting IL-1[beta] activity and safeguarding against damaging inflammation.

Non-cardiac chest pain (NCCP) is a common clinical problem however the pathophysiology remains poorly understood. Until the pathophysiology is more clearly understood, certain patients with NCCP continue to experience chest pain and seek frequent medical attention. This mini-review will discuss the underlying pathophysiology of NCCP including gastro-oesophageal reflux, oesophageal dysmotility and visceral hypersensitivity. Furthermore, it aims to highlight the current treatment options based on the current literature.

No abstract