Respiratory syncytial virus (RSV) is a major human respiratory pathogen, particularly for infants. RSV is also a powerful inducer of cytokines, one of which is IL-15, an important immunoregulatory cytokine. IL-15 plays a key role in NK and T cell development and differentiation and also regulates NK cell/macrophage interaction, as well as monocyte/macrophage and granulocyte function. We have shown previously that different viruses up-regulate IL-15 gene expression in human PBMCs. Recently, we found that RSV induces the expression of IL-15 mRNA in the monocytic line THP-1. The signaling pathway involved in such virus-induced up-regulation of IL-15 has not yet been identified. We report here a study describing this mechanism. Because of the involvement of the protein kinase C (PKC) and the transcription factor NF-κB in the regulation of others cytokines by RSV as well as the involvement of NF-κB in the transactivation of IL-15, our hypothesis was that RSV induced the expression of IL-15 in THP-1 cells through the PKC and NF-κB activation. We demonstrate here that RSV-induced up-regulation of IL-15 expression in THP-1 cells involves the phosphorylation of PKC-α/β. Further, inhibition of PKC by different specific inhibitors blocks this up-regulation. Using the electromobility shift assay, we show that the activated form of NF-κB binds to the IL-15 promoter sequence. We further confirm, using an ELISA assay, the involvement of p65 in the transcription of IL-15. This study, demonstrating the ability of RSV to induce IL-15 expression, might explain, at least in part, the exacerbated, inflammatory response triggered by RSV infection.