Interleukin-1α Activity in Necrotic Endothelial Cells Is Controlled by Caspase-1 Cleavage of Interleukin-1 Receptor-2: IMPLICATIONS FOR ALLOGRAFT REJECTION.
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.
From the Division of Cardiovascular Medicine, University of Cambridge, Level 6, Box 110, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
Laura C
LC
Burzynski
From the Division of Cardiovascular Medicine, University of Cambridge, Level 6, Box 110, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
Melanie
M
Humphry
From the Division of Cardiovascular Medicine, University of Cambridge, Level 6, Box 110, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
Martin R
MR
Bennett
From the Division of Cardiovascular Medicine, University of Cambridge, Level 6, Box 110, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom mchc2@cam.ac.uk.
Murray C H
MC
Clarke
D064591:Allografts / Q000276:immunology*; D002154:Calpain / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D006084:Graft Rejection / Q000378:metabolism* / Q000473:pathology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000378:metabolism*; D009336:Necrosis / Q000276:immunology; D059748:Proteolysis; D053574:Receptors, Interleukin-1 Type II / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C508584:IL1A protein, human; D007375:Interleukin-1; D053582:Interleukin-1alpha; D053574:Receptors, Interleukin-1 Type II; D014409:Tumor Necrosis Factor-alpha; D002154:Calpain; D020170:Caspase 1
calpain; caspase; endothelial cell; inflammation; interleukin 1 (IL-1); interleukin-1 receptor-2; necrosis (necrotic death); transplantation; vascular biology; vascular smooth muscle cells