Interleukin-1α Activity in Necrotic Endothelial Cells Is Controlled by Caspase-1 Cleavage of Interleukin-1 Receptor-2: IMPLICATIONS FOR ALLOGRAFT REJECTION

J Biol Chem. 2015 Oct 9;290(41):25188-96. doi: 10.1074/jbc.M115.667915. Epub 2015 Aug 31.

Abstract

Inflammation is a key instigator of the immune responses that drive atherosclerosis and allograft rejection. IL-1α, a powerful cytokine that activates both innate and adaptive immunity, induces vessel inflammation after release from necrotic vascular smooth muscle cells (VSMCs). Similarly, IL-1α released from endothelial cells (ECs) damaged during transplant drives allograft rejection. However, IL-1α requires cleavage for full cytokine activity, and what controls cleavage in necrotic ECs is currently unknown. We find that ECs have very low levels of IL-1α activity upon necrosis. However, TNFα or IL-1 induces significant levels of active IL-1α in EC necrotic lysates without alteration in protein levels. Increased activity requires cleavage of IL-1α by calpain to the more active mature form. Immunofluorescence and proximity ligation assays show that IL-1α associates with interleukin-1 receptor-2, and this association is decreased by TNFα or IL-1 and requires caspase activity. Thus, TNFα or IL-1 treatment of ECs leads to caspase proteolytic activity that cleaves interleukin-1 receptor-2, allowing IL-1α dissociation and subsequent processing by calpain. Importantly, ECs could be primed by IL-1α from adjacent damaged VSMCs, and necrotic ECs could activate neighboring normal ECs and VSMCs, causing them to release inflammatory cytokines and up-regulate adhesion molecules, thus amplifying inflammation. These data unravel the molecular mechanisms and interplay between damaged ECs and VSMCs that lead to activation of IL-1α and, thus, initiation of adaptive responses that cause graft rejection.

Keywords: calpain; caspase; endothelial cell; inflammation; interleukin 1 (IL-1); interleukin-1 receptor-2; necrosis (necrotic death); transplantation; vascular biology; vascular smooth muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts / immunology*
  • Calpain / metabolism
  • Caspase 1 / metabolism*
  • Graft Rejection / metabolism*
  • Graft Rejection / pathology*
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / immunology
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / pathology*
  • Humans
  • Interleukin-1 / pharmacology
  • Interleukin-1alpha / metabolism*
  • Necrosis / immunology
  • Proteolysis
  • Receptors, Interleukin-1 Type II / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • IL1A protein, human
  • Interleukin-1
  • Interleukin-1alpha
  • Receptors, Interleukin-1 Type II
  • Tumor Necrosis Factor-alpha
  • Calpain
  • Caspase 1