TAK1 regulates reactive oxygen species and cell death in keratinocytes, which is essential for skin integrity.
Mice with a keratinocyte-specific deletion of Tak1 exhibit severe skin inflammation due to hypersensitivity to tumor necrosis factor (TNF) killing. Here we have examined the mechanisms underlying this hypersensitivity. We found that TAK1 deficiency up-regulates reactive oxygen species (ROS) resulting in cell death upon TNF or oxidative stress challenge. Because blockade of NF-kappaB did not increase ROS or did not sensitize cells to oxidative stress in keratinocytes TAK1 regulates ROS mainly through the mechanisms other than those mediated by NF-kappaB. We found that c-Jun was decreased in TAK1-deficient keratinocytes and that ectopic expression of c-Jun could partially inhibit TNF-induced increase of ROS and cell death. Finally, we show that, in an in vivo setting, the antioxidant treatment could reduce an inflammatory condition in keratinocyte-specific Tak1 deletion mice. Thus, TAK1 regulates ROS partially through c-Jun, which is important for preventing ROS-induced skin inflammation.
Omori
Emily
E
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695-7633, USA.
Morioka
Sho
S
Matsumoto
Kunihiro
K
Ninomiya-Tsuji
Jun
J
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005786:Gene Expression Regulation; D007249:Inflammation; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D017382:Reactive Oxygen Species; D012867:Skin / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D000975:Antioxidants; D045304:Cytochromes c; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D000099151:MAP Kinase Kinase Kinase 7