Essential amino acid tryptophan inhibits induction of inducible nitric oxide synthase gene expression in interleukin-1β stimulated hepatocytes
Background: Tryptophan exerts protective effects against a variety of organ inflammation and injury, including the liver. However, there are few scientific reports about the mechanisms involved with the action. Pro-inflammatory cytokine interleukin (IL)-1β stimulates the induction of inducible nitric oxide synthase (iNOS) expression and NO production in cultured hepatocytes (“in vitro liver injury model”). Additionally, the prevention of iNOS expression and NO production is an indicator of liver protection. Thus, the study aimed to examine whether tryptophan influences the induction of iNOS gene expression and the mechanisms.
Methods: Tryptophan was added into primary cultures of rat hepatocytes stimulated by IL-1β. The iNOS induction, NO production, and its signaling pathway were analyzed.
Results: IL-1β induced iNOS gene expression, which was followed by iNOS expression and NO production. Tryptophan inhibited the expression of iNOS mRNA and protein, in addition to decreasing the production of NO. Transfection experiments with iNOS promoter-luciferase constructs revealed that tryptophan reduced the activities of iNOS mRNA synthesis and its stability. Tryptophan blocked two essential signaling pathways, the activation of nuclear factor (NF)-κB and upregulation of type I IL-1receptor (IL-1RI).
Conclusions: Results indicate that tryptophan can prevent the NO production by inhibition of iNOS gene expression, partly through NF-κB activation and IL-1RI upregulation in inflamed hepatocytes. Tryptophan may be a potential therapeutic treatment in injured organs, including the liver.
Keywords: tryptophan, inducible nitric oxide synthase, nitric oxide, cultured hepatocytes, nuclear factor-κB, type I interleukin-1 receptor
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Copyright (c) 2019 Takumi Tsuda, Hirokazu Miki, Richi Nakatake, Tatsuma Sakaguchi, Masahiko Hatta, Tadayoshi Okumura, Mikio Nishizawa, Masaki Kaibori
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