The role of endothelial interleukin-8/NADPH oxidase 1 axis in sepsis.
Sepsis is a generalized inflammatory disease, caused by the hyperinflammatory response of the host, rather than by invading organisms. Endothelial cells play a crucial role in the pathogenesis of sepsis. In this study, we investigated the effects of interleukin-8 (IL-8), a known neutrophil chemoattractant, on lipopolysaccharide (LPS) -induced reactive oxygen species (ROS) production by endothelial cells, and its significance in the pathogenesis of LPS-mediated sepsis. The results revealed that IL-8 directly induced ROS production in human umbilical vein endothelial cells (HUVECs), and also mediated LPS-induced ROS production by HUVECs. Stimulation of HUVECs by LPS strongly enhanced tissue factor expression, a hallmark of severe sepsis, which was suppressed by IL-8 knockdown. We further discovered that NADPH oxidase (Nox) 1 expression in LPS-stimulated HUVECs was markedly repressed by IL-8 knockdown, and Nox1 knockdown reduced tissue factor expression, suggesting that the LPS/IL-8 signalling in endothelial cells was predominantly mediated by Nox1. In conclusion, LPS stimulation of endothelial cells causes activation of the IL-8-Nox1 axis, enhances the production of ROS, and ultimately contributes to the progression of severe sepsis.
Department of Haematology and Oncology, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
Takashi
T
Miyoshi
Kouhei
K
Yamashita
Toshiyuki
T
Arai
Kokichi
K
Yamamoto
Kiyomi
K
Mizugishi
Takashi
T
Uchiyama
D002460:Cell Line; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism*; D018805:Sepsis / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013925:Thromboplastin / Q000096:biosynthesis / Q000235:genetics
D016209:Interleukin-8; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013925:Thromboplastin; D019255:NADPH Oxidases