UVB radiation induces apoptosis in keratinocytes by activating a pathway linked to "BLT2-reactive oxygen species".
The role of reactive oxygen species (ROS) in UVB-induced apoptosis has been established, but the molecular mechanisms of their production in response to UVB irradiation in keratinocytes are not well understood. In this study, we demonstrate that levels of BLT2, a low-affinity leukotriene B(4) receptor, and its ligands (LTB(4) and 12(S)-HETE) are greatly increased by UVB irradiation and are responsible for the UVB-induced ROS generation in human keratinocytes. Blockade of BLT2 with a BLT2-specific antagonist, LY255283, or with siBLT2 attenuated ROS production and apoptotic cell death detected by a number of criteria. Moreover, we found that the NADPH oxidase family protein Nox1 lies downstream of BLT2 and mediates UVB-induced ROS production and apoptosis. Topical treatment of mouse epidermal skin with LY255283 gave significant protection against UVB-induced sunburn-associated apoptotic damage. Finally, when BLT2-overexpressing transgenic mice were irradiated with UVB, we observed more extensive skin apoptosis. Taken together, our results demonstrate that a "BLT2-Nox1"-linked pathway has a crucial role in UVB-induced ROS generation and mediates apoptosis in human keratinocytes.
Ryu
Ho-Cheol
HC
School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
Kim
Cheolmin
C
Kim
Joo-Young
JY
Chung
Jin-Ho
JH
Kim
Jae-Hong
JH
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D002461:Cell Line, Transformed; D004817:Epidermis / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D020024:Leukotriene Antagonists / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology / Q000528:radiation effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D014466:Ultraviolet Rays
C485878:LTB4R2 protein, human; D020024:Leukotriene Antagonists; D017382:Reactive Oxygen Species; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles; D007975:Leukotriene B4; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C063823:LY 255283