Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of IκB kinase activity

Abstract

AbstractInterleukin-10 (IL-10) has potent immunoregulatory effects on the maturation and the antigen-presenting cell (APC) function of dendritic cells (DCs). The molecular basis underlying these effects in DCs, however, is ill defined. It is well established that the transcription factor NF-κB is a key regulator of DC development, maturation, and APC function. This study was initiated to determine the effects of IL-10 on the NF-κB signaling pathway in immature DCs. IL-10 pretreatment of myeloid DCs cultured from bone marrow resulted in reduced DNA binding and nuclear translocation of NF-κB after anti-CD40 antibody or lipopolysaccharide (LPS) stimulation. Furthermore, inhibited NF-κB activation was characterized by reduced degradation, phosphorylation, or both of IκBα and IκBϵ but not IκBβ and by reduced phosphorylation of Ser536, located in the trans-activation domain of p65. Notably, IL-10–mediated inhibition of NF-κB coincided with suppressed IκB kinase (IKK) activity in vitro. Furthermore, IL-10 blocked inducible Akt phosphorylation, and inhibitors of phosphatidylinositol 3-kinase (PI3K) effectively suppressed the activation of Akt, IKK, and NF-κB. These findings demonstrate that IL-10 targets IKK activation in immature DCs and that suppressing the PI3K pathway in part mediates blockade of the pathway.