Cardamonin suppresses nitric oxide production via blocking the IFN-γ/STAT pathway in endotoxin-challenged peritoneal macrophages of ICR mice.

AIMS

Overproduction of nitric oxide (NO) from inducible NO synthase (iNOS) plays many pivotal roles in various inflammatory diseases. In this study, we examined the effects of 6 flavonoids on lipopolysaccharide (LPS)-induced NO generation in macrophage (Mφ), and addressed molecular mechanisms of cardamonin.

MAIN METHODS

Suppressive effects on NO generation in vitro were assayed in LPS-stimulated macrophages (Mφ). In vivo anti-inflammatory activity was evaluated with LPS-challenged ICR mice. Mechanistic analyses were done by ELISA, Western blot, RT-PCR, etc.

KEY FINDINGS

Cardamonin, a chalcone, exhibited pronounced suppressive activity, while pinocembrin, a counterpart flavanone, was much less active. Administration of cardamonin (0.02-2 mg/kg body weight) significantly decreased NOx concentrations in the sera from LPS-challenged ICR mice. This efficacy was superior to that of curcumin, a well-known anti-inflammatory agent present in turmeric. Cardamonin down-regulated iNOS mRNA expression and suppressed activation of STAT-1, but not nuclear factor kappaB, both of which are transcription factors for the iNOS gene in peritoneal Mφ of ICR mice. Interferon (IFN)-γ was identified as the major cytokine which mediates LPS-induced STAT-1 activation and resultant iNOS expression. Intriguingly, cardamonin suppressed the activation of not only STAT-1 but also STATs-2, 3 and 4. The involvement of the JAK/STATs pathway in NO generation was suggested because its specific inhibitor, AG490, decreased NO generation.

SIGNIFICANCE

Cardamonin was identified to be a unique phytochemical that targets the production of IFN- and thereby suppresses the STAT pathway for mitigating inflammation.