title: TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice.
abstract: The role of TRAF2 and TRAF5 in TNFα-induced NF-κB activation has become complicated owing to the accumulation of conflicting data. Here, we report that 7-day-old TRAF2-knockout (KO) and TRAF2 TRAF5 double KO (TRAF2/5-DKO) mice exhibit enhanced canonical IκB kinase (IKK) and caspase-8 activation in spleen and liver, and that subsequent knockout of TNFα suppresses the basal activity of caspase-8, but not of IKK. In primary TRAF2 KO and TRAF2/5-DKO cells, TNFα-induced immediate IKK activation is impaired, whereas delayed IKK activation occurs normally; as such, owing to elevated basal and TNFα-induced delayed IKK activation, TNFα stimulation leads to significantly increased induction of a subset of NF-κB-dependent genes in these cells. In line with this, both TRAF2 KO and TRAF2/5-DKO mice succumb to a sublethal dose of TNFα owing to increased expression of NF-κB target genes, diarrhea and bradypnea. Notably, depletion of IAP1 and IAP2 (also known as BIRC2 and BIRC3, respectively) also results in elevated basal IKK activation that is independent of autocrine TNFα production and that impairs TNFα-induced immediate IKK activation. These data reveal that TRAF2, IAP1 and IAP2, but not TRAF5, cooperatively regulate basal and TNFα-induced immediate IKK activation.
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
authors.forename: Laiqun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Blackwell
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Workman
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Gibson-Corley
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.affiliation: Department of Microbiology & Internal Medicine, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
authors.forename: Gail A
authors.initials: GA
authors.lastname: Bishop
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA hasem-habelhah@uiowa.edu.
authors.forename: Hasem
authors.initials: H
authors.lastname: Habelhah
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D053181:Caspase 8 / Q000378:metabolism*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D051034:Inhibitor of Apoptosis Proteins / Q000172:deficiency; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D048015:TNF Receptor-Associated Factor 5 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494834:Birc2 protein, mouse; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase; D053181:Caspase 8
keywords: Apoptosis; NF-κB; TNFα; TRAF2; TRAF5