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Effect of Thiol-Containing Molecule Cysteamine on the Induction of Inducible Nitric Oxide Synthase in Hepatocytes

Takashi Ozaki, MD, PhD^*, Masaki Kaibori, MD, PhD^*, Kosuke Matsui, MD, PhD^*, Katsuji Tokuhara, MD^*, Hironori Tanaka, MD^*, Yasuo Kamiyama, MD, PhD^*, Mikio Nishizawa, MD, PhD, Seiji Ito, MD, PhD and Tadayoshi Okumura, PhD

From the ^* Department of Surgery and the Department of Medical Chemistry, Kansai Medical University, Moriguchi, Osaka, Japan

Correspondence: Tadayoshi Okumura, PhD, Department of Medical Chemistry, Kansai Medical University, 10–15 Fumizonocho, Moriguchi, Osaka 570-8506, Japan. Electronic mail may be sent to okumura{at}takii.kmu.ac.jp.

Background: Cysteamine, which is a known antioxidant and anti-inflammatory agent, is believed to be a key regulator of essential metabolic pathways in organisms. Cysteamine has beneficial effects in liver damaged by a variety of insults. During liver injury, inducible nitric oxide synthase (iNOS) is induced by lipopolysaccharide or proinflammatory cytokines, leading to excessive nitric oxide (NO) production. Accumulated evidence indicates that NO is an important factor associated with hepatic dysfunction. We examined whether cysteamine influences the induction of iNOS in hepatocytes. Methods: Primary cultured rat hepatocytes were treated with interleukin (IL)-1β in the presence and absence of cysteamine. NO production, iNOS induction, and iNOS signal were analyzed. Results: IL-1β stimulated the inhibitory protein B (IB)/nuclear factor B (NFB) pathway, resulting in the activation of NFB (nuclear translocation and DNA binding), which was followed by the induction of iNOS and NO production. The addition of IL-1β and cysteamine (1–4 mmol/L) markedly inhibited NO production, with a maximal effect at 4 mmol/L (80%–90% inhibition). Cysteamine also decreased the levels of iNOS protein and mRNA. Transfection experiments revealed that cysteamine decreased the transactivation activity of the iNOS promoter. An electrophoretic mobility shift assay demonstrated that cysteamine inhibited the activation of NFB. Furthermore, cysteamine decreased the mRNA levels of the NFB subunit p65 but increased those of the inhibitory protein IB. Conclusions: These findings suggest that cysteamine inhibits iNOS induction at the step of NFB activation. Further study is necessary to define the molecular basis of this effect of cysteamine on the regulation of NFB and its pharmacologic implications.

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Journal of Parenteral and Enteral Nutrition, Vol. 31, No. 5, 366-372 (2007)
DOI: 10.1177/0148607107031005366


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