Deletion of IKK2 in haematopoietic cells of adult mice leads to elevated interleukin-6, neutrophilia and fatal gastrointestinal inflammation |
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Authors: | Karla C. Fischer,Carmel P. Daunt,Cé dric S. Tremblay,Sheila Dias,James E. Vince,Anissa M. Jabbour |
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Affiliation: | 1.The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC Australia ;2.Department of Medical Biology, University of Melbourne, Parkville, VIC Australia ;3.Australian Centre for Blood Diseases, Monash University, Melbourne, VIC Australia |
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Abstract: | The IκB kinase complex, consisting of IKK1, IKK2 and the regulatory subunit NEMO, is required for NF-κB signalling following the activation of several cell surface receptors, such as members of the Tumour Necrosis Factor Receptor superfamily and the Interleukin-1 Receptor. This is critical for haematopoietic cell proliferation, differentiation, survival and immune responses. To determine the role of IKK in the regulation of haematopoiesis, we used the Rosa26Cre-ERT2 Cre/lox recombination system to achieve targeted, haematopoietic cell-restricted deletion of the genes for IKK1 or IKK2 in vivo. We found that the IKK complex plays a critical role in haematopoietic cell development and function. Deletion of IKK2, but not loss of IKK1, in haematopoietic cells led to an expansion of CD11b/Gr-1-positive myeloid cells (neutrophilia), severe anaemia and thrombocytosis, with reduced numbers of long-term haematopoietic stem cells (LT-HSCs), short-term haematopoietic stem cells (ST-HSCs) and multipotential progenitor cells (MPPs), increased circulating interleukin-6 (IL-6) and severe gastrointestinal inflammation. These findings identify distinct functions for the two IKK catalytic subunits, IKK1 and IKK2, in the haematopoietic system.Subject terms: Growth factor signalling, Interleukins, Myelopoiesis, Inflammatory diseases, Haematopoietic stem cells |
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