Interleukin (IL)-15 is an important inflammatory cytokine and plays a key role in autoimmune disease. At present, IL-15 gene expression and regulation related to many innate immunity trigger signals have been clarified in some specific cell types, but the relationship of IL-6 and IL-15 in the human keratinocyte cell line (HaCaT) is unknown. In this study, we investigated the effect of IL-6 on the expression of IL-15 and selected signaling pathways in HaCaT cells. Results demonstrated that IL-6 up-regulated the expression of IL-15 both at the mRNA and protein levels. Meanwhile, IL-6 was able to activate MAPKs-ERK1/2 and PI3K-AKT signaling pathways. Furthermore, the high expression of IL-15 induced by IL-6 was down-regulated while MAPKs-ERK1/2 and PI3K-AKT signaling pathways were, respectively, blocked by PD98059 and LY294002. These findings indicate that the expression of IL-15 up-regulated by IL-6 is associated with MAPKs-ERK1/2 and PI3K-AKT signaling pathways in HaCaT cells.