Neurokinin A (NKA) belongs to the tachykinin neuropeptide family. Its biological functions are primarily mediated by the neurokinin (NK)-2 receptor. NKA has been implicated in several inflammatory conditions. However, there are limited data about the mechanism of its pathogenetic action. Here, we investigated proinflammatory effects of NKA on peripheral immune cells using a mouse macrophage/monocyte cell line RAW264.7 and primary peritoneal macrophages. The signaling mechanistic pathways involved was also studied. In mouse macrophages with no detectable NK-2 receptors, NKA induces the upregulation of NK-1 but not NK-2 receptor expression. Furthermore, NKA engages this NK-1 receptor resulting in inflammatory-like responses involving activation of the transcription factor NF-B and induction of NF-B-responsive proinflammatory chemokine expression. NKA activates NF-B as evidenced by induced phosphorylation (leading to degradation) of its inhibitory protein IB, increased cellular levels of the transactivation-active phospho(Ser276)-p65 and its nuclear translocation, as well as enhanced DNA-binding activity of nuclear NF-B. These responses are specifically inhibited by selective NK-1 receptor antagonists but not NK-2 receptor antagonists thereby excluding the role of NK-2 receptor. Further investigation on the upstream signaling mechanisms suggests two NF-B-activating pathways ERK1/2 and PI3K/Akt are activated by NKA. Specific inhibitors of the two pathways block NF-B-dependent chemokine expression. The inhibitory effects are mediated through regulation of nuclear translocation, DNA-binding activity and/or transactivation activity of NF-B. Together, we provide novel evidence that NKA engages NK-1 receptors on mouse macrophages to elicit NF-B-dependent cellular responses. The findings reveal cellular mechanisms that may underlie NKA-mediated inflammatory and immunological conditions.