Title:Genipin Inhibits the Induction of Inducible Nitric Oxide Synthase Through the Inhibition of NF-κB Activation in Rat Hepatocytes
VOLUME: 10 ISSUE: 4
Author(s):Richi Nakatake, Takumi Tsuda, Takashi Matsuura, Hirokazu Miki, Hidehiko Hishikawa, Hideyuki Matsushima, Morihiko Ishizaki, Kosuke Matsui, Masaki Kaibori, Mikio Nishizawa, Tadayoshi Okumura* and Masanori Kon
Affiliation:Department of Surgery, Kansai Medical University, Hirakata, Osaka, Department of Surgery, Kansai Medical University, Hirakata, Osaka, Department of Surgery, Kansai Medical University, Hirakata, Osaka, Department of Surgery, Kansai Medical University, Hirakata, Osaka, Department of Surgery, Kansai Medical University, Hirakata, Osaka, Department of Surgery, Kansai Medical University, Hirakata, Osaka, Department of Surgery, Kansai Medical University, Hirakata, Osaka, Department of Surgery, Kansai Medical University, Hirakata, Osaka, Department of Surgery, Kansai Medical University, Hirakata, Osaka, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan, Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 573-1010, Department of Surgery, Kansai Medical University, Hirakata, Osaka
Keywords:Genipin, inducible nitric oxide synthase, nuclear factor- κB, primary cultured hepatocytes, tumor necrosis factor-α, type I interleukin-1 receptor.
Abstract:Background/Aims: Genipin is a component of Japanese traditional herbal medicine
(Kampo), inchinkoto, and is used for the treatment of various liver injuries. However, there are few scientific
evidence for its anti-inflammatory effects and mechanisms. In inflamed liver, proinflammatory
cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β stimulate liver cells, followed
by the expression of inducible nitric oxide synthase (iNOS). Excessive levels of NO produced by
iNOS have been implicated as one of the factors in liver injury. Thus it is essential to inhibit iNOS induction
for the prevention of liver injury. In this study, we examined IL-1β-stimulated hepatocytes as a
simple “in vitro liver injury model” to investigate liver protective effects of genipin.
Methods: Primary cultured rat hepatocytes were treated with IL-1β in the presence or absence of
genipin. The induction of NO production and iNOS, and its signaling pathway were analyzed.
Results: In IL-1β-stimulated hepatocytes, genipin inhibited the production of NO dose- and timedependently,
and reduced the levels of iNOS protein and its mRNA expression. Genipin also reduced
mRNA expressions of TNF-α and IL-6. Genipin inhibited two essential signaling pathways for iNOS
induction, IκB degradation/NF-κB activation and type I IL-1 receptor upregulation. Transfection experiments
revealed that genipin decreased the expression of iNOS mRNA through both inhibitions of
the promoter activation and mRNA stabilization. Delayed administration of genipin after IL-1β addition
also inhibited iNOS induction.
Conclusion: Genipin influenced the induction of inflammatory mediators, iNOS and TNF-α, in part
through the inhibition of NF-κB activation in hepatocytes. Genipin may have therapeutic potential for
organ injuries including liver.
