title: Myeloid TAKI [corrected] acts as a negative regulator of the LPS response and mediates resistance to endotoxemia.
abstract: TGFβ-activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, is considered a key intermediate in a multitude of innate immune signaling pathways. Yet, the specific role of TAK1 in the myeloid compartment during inflammatory challenges has not been revealed. To address this question, we generated myeloid-specific kinase-dead TAK1 mutant mice. TAK1 deficiency in macrophages results in impaired NF-κB and JNK activation upon stimulation with lipopolysaccharide (LPS). Moreover, TAK1-deficient macrophages and neutrophils show an enhanced inflammatory cytokine profile in response to LPS stimulation. Myeloid-specific TAK1 deficiency in mice leads to increased levels of circulating IL-1β, TNF and reduced IL-10 after LPS challenge and sensitizes them to LPS-induced endotoxemia. These results highlight an antiinflammatory role for myeloid TAK1, which is essential for balanced innate immune responses and host survival during endotoxemia.
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Eftychi
authors.forename: Niki
authors.initials: N
authors.lastname: Karagianni
authors.forename: Maria
authors.initials: M
authors.lastname: Alexiou
authors.forename: Maria
authors.initials: M
authors.lastname: Apostolaki
authors.forename: George
authors.initials: G
authors.lastname: Kollias
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D019446:Endotoxemia / Q000276:immunology*; D007113:Immunity, Innate; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B; D009504:Neutrophils / Q000276:immunology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D016207:Cytokines; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D000099151:MAP Kinase Kinase Kinase 7