cIAPs and XIAP regulate myelopoiesis through cytokine production in a RIPK1 and RIPK3 dependent manner
- Wong, WW; Vince, JE; Lalaoui, N; Lawlor, KE; Chau, D; Bankovacki, A; Anderton, H; Metcalf, D; O'Reilly, L; Jost, PJ; Murphy, JM; Alexander, WS; Strasser, A; Vaux, DL; Silke, J;
Publication Year 2014-02-04, Volume 123, Issue #16, Page 2562-72
- Journal Title
- Publication Type
- Journal Article
- Loss of Inhibitor of Apoptosis (IAP) proteins, particularly cIAP1, can promote production of tumor necrosis factor (TNF) and sensitize cancer cell lines to TNF induced necroptosis by promoting formation of a death inducing signaling complex containing receptor-interacting serine/threonine-protein kinase 1 and 3 (RIPK1, RIPK3). To define the role of IAPs in myelopoiesis, we generated a mouse with cIAP1, cIAP2 and XIAP deleted in the myeloid lineage. Loss of cIAPs and XIAP in the myeloid lineage caused over-production of many pro-inflammatory cytokines, resulting in granulocytosis and severe sterile inflammation. In vitro differentiation of macrophages from bone marrow in the absence of cIAPs and XIAP led to detectable levels of TNF and resulted in reduced numbers of mature macrophages. The cytokine production and consequent cell death caused by IAP depletion was attenuated by loss or inhibition of TNF or TNFR1. The loss of RIPK1 or RIPK3, but not the RIPK3 substrate MLKL, attenuated TNF secretion and thereby prevented apoptotic cell death and not necrosis. Our results demonstrate that cIAPs and XIAP together restrain RIPK1 and RIPK3 dependent cytokine production in myeloid cells to critically regulate myeloid homeostasis.
- AMER SOC HEMATOLOGY
- WEHI Research Division(s)
- Molecular Genetics Of Cancer; Cell Signalling And Cell Death; Cancer And Haematology
- Publisher's Version
- Rights Notice
- Copyright 2011 by The American Society of Hematology; all rights reserved.
Creation Date: 2014-02-18 01:00:23Last Modified: 2015-09-07 10:30:45