Melatonin inhibits visfatin-induced inducible nitric oxide synthase expression and nitric oxide production in macrophages
Melatonin inhibits visfatin-induced inducible nitric oxide synthase expression and nitric oxide production in macrophages
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DOI：
10.1111/jpi.12072
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发表时间：
2013-10-01
影响因子：
10.3
通讯作者：
Bae, Soo-Kyung
中科院分区：
文献类型：
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作者：
Kang, Young-Soon;Kang, Yong-Gyu;Bae, Soo-Kyung
巨噬细胞中诱导型一氧化氮合酶（iNOS）的异常表达在病理性炎症的发展中具有重要作用，据报道其被褪黑素抑制。内脂素是一种脂肪因子，调节多种炎症因子的表达，导致炎症;然而，内脂素对巨噬细胞中iNOS驱动的过程的影响尚不清楚。在这里，我们报告的内脂素在巨噬细胞中的iNOS基因表达的调节作用的评估。我们的数据表明，腹腔巨噬细胞中的iNOS蛋白的水平以及血浆中的一氧化氮（NO）的水平显着降低后，内脂素（+/-）小鼠的脂多糖治疗比WT小鼠。此外，内脂素增加iNOS mRNA和蛋白水平在RAW 264.7细胞，沿着增加NO的产生。iNOS表达的增强被阻止与Janus激酶2/信号转导和转录激活因子3（JAK 2/STAT 3），核因子（NF）-B，细胞外信号调节激酶1/2和c-Jun N-末端激酶途径的抑制剂处理细胞。我们的研究结果还表明，visfatin诱导的iNOS表达和NO的产生显着抑制褪黑激素，这种效果是密切相关的磷酸化JAK 2/STAT 3水平的降低和抑制p65易位到细胞核。总之，我们的数据表明，第一次，褪黑激素抑制visfatin诱导的诱导型一氧化氮合酶上调巨噬细胞通过抑制STAT 3和NF-B途径。此外，我们的数据表明，褪黑激素可能是治疗上有用的衰减visfatin-iNOS轴相关疾病的发展。
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 264.7cells, 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)-B, 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-B pathways. Moreover, our data suggest that melatonin could be therapeutically useful for attenuating the development of visfatin-iNOS axis-associated diseases.