Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation

Immunity. 2012 Feb 24;36(2):215-27. doi: 10.1016/j.immuni.2012.01.012.

Abstract

Interleukin-1β (IL-1β) is a potent inflammatory cytokine that is usually cleaved and activated by inflammasome-associated caspase-1. To determine whether IL-1β activation is regulated by inhibitor of apoptosis (IAP) proteins, we treated macrophages with an IAP-antagonist "Smac mimetic" compound or genetically deleted the genes that encode the three IAP family members cIAP1, cIAP2, and XIAP. After Toll-like receptor priming, IAP inhibition triggered cleavage of IL-1β that was mediated not only by the NLRP3-caspase-1 inflammasome, but also by caspase-8 in a caspase-1-independent manner. In the absence of IAPs, rapid and full generation of active IL-1β by the NLRP3-caspase-1 inflammasome, or by caspase-8, required the kinase RIP3 and reactive oxygen species production. These results demonstrate that activation of the cell death-inducing ripoptosome platform and RIP3 can generate bioactive IL-1β and implicate them as additional targets for the treatment of pathological IL-1-driven inflammatory responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Carrier Proteins / agonists
  • Carrier Proteins / metabolism
  • Caspase 1 / metabolism
  • Inflammasomes / immunology
  • Inflammasomes / metabolism
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Inhibitor of Apoptosis Proteins / deficiency
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Interleukin-1beta / metabolism*
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Mitochondrial Proteins / agonists
  • Molecular Mimicry
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Reactive Oxygen Species / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Ubiquitin-Protein Ligases
  • X-Linked Inhibitor of Apoptosis Protein / deficiency
  • X-Linked Inhibitor of Apoptosis Protein / genetics
  • X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Diablo protein, mouse
  • Inflammasomes
  • Inhibitor of Apoptosis Proteins
  • Interleukin-1beta
  • Mitochondrial Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Reactive Oxygen Species
  • X-Linked Inhibitor of Apoptosis Protein
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Birc2 protein, mouse
  • Birc3 protein, mouse
  • Ubiquitin-Protein Ligases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • Caspase 1