Journal of hepatology · 2007
Epimorphin, a morphogenic protein, induces proteases in rodent hepatocytes through NF-kappaB.
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Miura Kouichi, Yoshino Ryutaro, Hirai Yohei, Goto Takashi, Ohshima Shigetoshi, Mikami Ken-Ichiro, Yoneyama Kazuo, Watanabe Daisuke, Sato Mitsuru, Senoo Haruki, Kodama Yuzo, Osawa Yosuke, Brenner David A, Watanabe Sumio
Аннотация
BACKGROUND/AIMS: Epimorphin, expressed by hepatic stellate cells in the liver, directs normal morphogenesis in various organs. The aim of this study was to clarify the mechanism by which epimorphin functions as a morphogen in vitro.
METHODS: Male Balb/c mice and Sprague-Dawley rats were used. First, we explored the relationship between epimorphin expression and distribution of protease-positive cells in carbon tetrachloride-induced acute liver injury. We then examined protease levels in cultured hepatocytes and signal transduction of epimorphin. Finally, we determined the requirement for proteases and NF-kappaB in spheroid formation induced by epimorphin.
RESULTS: Epimorphin expression was enhanced in injured areas during late recovery phase, in which protease-positive hepatocytes were localized adjacent to epimorphin-expressing cells. In vitro, epimorphin induced matrix metalloproteinase (MMP) 9, MMP 3 and urokinase type plasminogen activator (uPA) in hepatocytes. NF-kappaB mediated these protease expressions in hepatocytes. These proteases were required for epimorphin-induced and Matrigel induced spheroid. An epimorphin-neutralizing antibody also blocked spheroid formation on Matrigel, which contained epimorphin. In addition, NF-kappaB activation was also required for spheroid formation.
CONCLUSION: Epimorphin elicits hepatocyte spheroids by inducing proteases in rodent hepatocytes through NF-kappaB.
METHODS: Male Balb/c mice and Sprague-Dawley rats were used. First, we explored the relationship between epimorphin expression and distribution of protease-positive cells in carbon tetrachloride-induced acute liver injury. We then examined protease levels in cultured hepatocytes and signal transduction of epimorphin. Finally, we determined the requirement for proteases and NF-kappaB in spheroid formation induced by epimorphin.
RESULTS: Epimorphin expression was enhanced in injured areas during late recovery phase, in which protease-positive hepatocytes were localized adjacent to epimorphin-expressing cells. In vitro, epimorphin induced matrix metalloproteinase (MMP) 9, MMP 3 and urokinase type plasminogen activator (uPA) in hepatocytes. NF-kappaB mediated these protease expressions in hepatocytes. These proteases were required for epimorphin-induced and Matrigel induced spheroid. An epimorphin-neutralizing antibody also blocked spheroid formation on Matrigel, which contained epimorphin. In addition, NF-kappaB activation was also required for spheroid formation.
CONCLUSION: Epimorphin elicits hepatocyte spheroids by inducing proteases in rodent hepatocytes through NF-kappaB.