Dendritic cells (DCs) are antigen-presenting cells that provide a link between innate and adaptive immunity by releasing several inflammatory mediators including interleukin 12 (IL-12). The release of IL-12 is important for Th1 polarization and is dependent on activation of Kv channels. Phosphoinositide 3 (PI3) kinase is an endogenous suppressor of IL-12 production in DCs. Little is known about the mechanisms linking PI3 kinase and IL-12 release. The downstream signaling elements of PI3 kinase include the serum- and glucocorticoid-inducible kinase-1 (SGK1). The present study, therefore, explored whether Kv channels and IL-12 release in DCs are influenced by SGK1. To this end, DCs were isolated from the bone marrow of gene targeted mice lacking functional SGK1 (sgk1-/- ) and their wild type littermates (sgk1+/+) and activated by lipopolysaccharide (LPS). Both, prior to and following LPS treatment, Kv channel activity was significantly higher in sgk1-/- than in sgk1+/+ DCs. The release of IL-12 and the surface expression of the costimulatory molecule CD86 and MHC class II were stimulated by LPS, an effect significantly stronger in sgk1-/- than in sgk1+/+ DCs. The observations point to a role for SGK1 in the regulation of Kv channels, maturation and cytokine release from DCs, and thus disclose a novel element in the cross-talk between innate and adaptive immunity.