A lifelong love affair with IL-1 and inflammation — ASN Events

A lifelong love affair with IL-1 and inflammation (#S-38)

Luke O'Neill 1
  1. Trinity College Dublin, Dublin, Ireland

IL-1 was one of the first cytokines to be described, first as a bioactivity that mediated inflammation in many different disease contexts, and then as a family of proteins – IL-1alpha, IL-1beta and the IL1 receptor antagonist. By the late 1980s IL-1 was known to induce the expression of a large number of immune and inflammatory genes and a key mystery was how it signals. Great detail into the signalling pathways leading to NF-kappaB and p38 MAP kinase then emerged. The IL-1 receptor was the founder member of the IL-1R/TLR superfamily and was first defined in detail 15 years ago. Since then, there has been remarkable progress in our understanding of both branches of the superfamily. Ligands have been described for most receptors. Within the IL-1R subfamily, notable examples include IL33 for ST2 and IL-36 for IL-1Rrp2.

The role of TLRs in the sensing of microbial products led to a renaissance of interest in innate immune mechanisms and represented one of the biggest advances in our understanding of the immune system over the past 50 years. For investigators interested in signal transduction, the area has proved very fruitful in terms of the discovery of new signalling pathways and processes, notably the MyD88 family of adapter proteins and the IRAK family, involving a complex series of ubiquitination and phosphorylation reactions.

Studies on how the-pro form of IL-1beta is processed led the description of inflammasomes, multiprotein complexes that activate caspase-1. Inflammasomes can also trigger a type of cell death dubbed pyroptosis. The best understood inflammasome comprises Nlrp3, and this protein has been implicated in all of the pathologies suggested to involve IL-1 in the 1980s which even then included gout, atherosclerosis, Alzheimer’s disease and Type 2 diabetes.

We therefore have a love story beginning as an ill-defined pro-inflammatory factor in supernatants from LPS-activated macrophags, to a revolution in innate immunity, and the real prospect of limiting the IL-1 system for substantial clinical benefit.