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SHR Neuro Krebs Kardio Lipid Stoffw Microb

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.
cIAPs and XIAP regulate myelopoiesis through cytokine production in an RIPK1- and RIPK3-dependent manner.
Blood. 2014; 123(16):2562-2572 Doi: 10.1182/blood-2013-06-510743 [OPEN ACCESS]
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Jost Philipp

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Loss of inhibitor of apoptosis proteins (IAPs), 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 (RIPK) 1 and 3. 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 overproduction of many proinflammatory 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 TNF receptor 1. The loss of RIPK1 or RIPK3, but not the RIPK3 substrate mixed lineage kinase domain-like protein, 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.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Apoptosis - genetics
Cells, Cultured -
Cytokines - metabolism
Gene Deletion -
Granulocytes - physiology
Inflammation - genetics
Inflammation - metabolism
Inhibitor of Apoptosis Proteins - physiology
Mice -
Mice, Inbred C57BL -
Mice, Knockout -
Myelopoiesis - genetics
Receptor-Interacting Protein Serine-Threonine Kinases - physiology
Splenomegaly - genetics
Splenomegaly - metabolism
X-Linked Inhibitor of Apoptosis Protein - physiology

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