Neuropeptide FF (NPFF) interacts with specific receptors to regulate diverse biological processes. Its modulatory
effect in the immune field, however, has not been fully explored yet. Here, we report that NPFF2 receptors may be
functionally expressed in two immune cell models, the primary peritoneal macrophage and RAW 264.7 macrophage.
Firstly, the mRNA levels of NPFF2 receptor were up-regulated in macrophages when treated with LPS for 24 to 72 h.
Subsequently, our data hinted that NPFF regulates the viability of both kinds of macrophages. After treatment with RF9, a
reported antagonist for both NPFF receptors, delayed or inhibited the NPFF-induced macrophages viability augmentation,
suggesting the involvement of NPFF2 receptor. Furthermore, down-regulation of nitric oxide (NO) synthases (NOSs) partially
significantly inhibited the viability augmentation of macrophages induced by NPFF, implying a nitric oxide synthases-
dependent pathway is involved. However, the NOSs are not the only route by which NPFF affects the viability of
macrophages. Pharmacological inhibitors of NF-κB signal pathway also blocked the NPFF-induced macrophages
growth, suggesting the involvement of the NF-κB signal pathway. The regulation activity of NPFF for macrophages suggests
that NPFF could act as a potential hormone in the control of immune system. Collectively, our data provide new
evidence about the immune modulatory effect of NPFF, which will be helpful in extending the scope of NPFF functions.