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J Pineal Res. 2013 Oct;55(3):294-303. doi: 10.1111/jpi.12072. Epub 2013 Jul 22.

Melatonin inhibits visfatin-induced inducible nitric oxide synthase expression and nitric oxide production in macrophages.

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Department of Dental Pharmacology, School of Dentistry, Yangsan Campus of Pusan National University, Yangsan, South Korea.


Aberrant expression of inducible nitric oxide synthase (iNOS) in macrophages, which has been reported to be suppressed by melatonin, has an important contribution in the development of pathological inflammation. Visfatin, an adipokine, regulates the expression of various inflammatory factors, leading to inflammation; however, the influence of visfatin on iNOS-driven processes in macrophages is unclear. Here, we report the assessment of the role of visfatin in the regulation of iNOS gene expression in macrophages. Our data show that the levels of iNOS protein in peritoneal macrophages as well as nitric oxide (NO) in blood plasma were significantly lower after lipopolysaccharide treatment in visfatin(+/-) mice than those in the WT mice. In addition, visfatin increases iNOS mRNA and protein levels in RAW 264.7 cells, along with increasing production of NO. The enhancement of iNOS expression was prevented by treating the cells with inhibitors of the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3), nuclear factor (NF)-κB, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase pathways. Our results also show that visfatin-induced iNOS expression and NO production were significantly inhibited by melatonin, an effect that was closely associated with a reduction in phosphorylated JAK2/STAT3 levels and with the inhibition of p65 translocation into nucleus. In conclusion, our data show, for the first time, that melatonin suppresses visfatin-induced iNOS upregulation in macrophages by inhibiting the STAT3 and NF-κB pathways. Moreover, our data suggest that melatonin could be therapeutically useful for attenuating the development of visfatin-iNOS axis-associated diseases.


NF-κB; STAT3; inducible nitric oxide synthase; macrophages; melatonin; visfatin

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