title: TAK1 inhibition-induced RIP1-dependent apoptosis in murine macrophages relies on constitutive TNF-α signaling and ROS production.
abstract: BACKGROUND
  Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a key regulator of signal cascades of TNF-α receptor and TLR4, and can induce NF-κB activation for preventing cell apoptosis and eliciting inflammation response.
  
  
  RESULTS
  TAK1 inhibitor (TAKI) can decrease the cell viability of murine bone marrow-derived macrophages (BMDM), RAW264.7 and BV-2 cells, but not dermal microvascular endothelial cells, normal human epidermal keratinocytes, THP-1 monocytes, human retinal pigment epithelial cells, microglia CHME3 cells, and some cancer cell lines (CL1.0, HeLa and HCT116). In BMDM, TAKI-induced caspase activation and cell apoptosis were enhanced by lipopolysaccharide (LPS). Moreover, TAKI treatment increased the cytosolic and mitochondrial reactive oxygen species (ROS) production, and ROS scavengers NAC and BHA can inhibit cell death caused by TAKI. In addition, RIP1 inhibitor (necrostatin-1) can protect cells against TAKI-induced mitochondrial ROS production and cell apoptosis. We also observed the mitochondrial membrane potential loss after TAKI treatment and deterioration of oxygen consumption upon combination with LPS. Notably TNF-α neutralization antibody and inhibitor enbrel can decrease the cell death caused by TAKI.
  
  
  CONCLUSIONS
  TAKI-induced cytotoxicity is cell context specific, and apoptosis observed in macrophages is dependent on the constitutive autocrine action of TNF-α for RIP1 activation and ROS production.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, No 1, Sec 1, Jen-Ai Road, Taipei, Taiwan.|Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jang-Shiun
authors.initials: JS
authors.lastname: Wang
authors.affiliation: Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
authors.forename: Dean
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, No 1, Sec 1, Jen-Ai Road, Taipei, Taiwan.
authors.forename: Duen-Yi
authors.initials: DY
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, No 1, Sec 1, Jen-Ai Road, Taipei, Taiwan. wwllaura1119@ntu.edu.tw.|Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan. wwllaura1119@ntu.edu.tw.
authors.forename: Wan-Wan
authors.initials: WW
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D017382:Reactive Oxygen Species / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020690:GTPase-Activating Proteins; D020930:MAP Kinase Kinase Kinases; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C490620:Ralbp1 protein, mouse