Leptin induces CD40 expression through the activation of Akt in murine dendritic cells

Increasing evidence suggests a regulatory role for leptin, an adipocyte-derived hormone, in immunity. Although recent studies indicated an essential role of leptin signaling in dendritic cell (DC) maturation, the molecular mechanisms by which leptin modulates DC functional maturation remained unclear. In this study, we showed that leptin induced CD40 expression in murine DC and significantly up-regulated their immunostimulatory function in driving T cell proliferation. Moreover, leptin markedly enhanced lipopolysaccharide-mediated DC activation. Using pharmacological inhibitors for Akt, STAT-1 alpha, or NF-kappa B and the dominant negative forms of Akt and I kappa B kinase alpha/beta/gamma,,y, as well as small interfering RNA for STAT-1 alpha, we showed that Akt, STAT-1 alpha, and NF-kappa B were important for the leptin- or lipopolysaccharide-induced CD40 expression. Coimmunoprecipitation analysis revealed that leptin promoted immune complex formation between Akt and the I kappa B kinase subunits as well as STAT-1 alpha. Blocking the activity of Akt demonstrated a crucial role for Akt in translocation of STAT-1 alpha and NF-kappa B to the nucleus and activation of the CD40 promoter. Further analysis with chromatin immunoprecipitation assay confirmed that leptin recruited STAT-1 alpha, NF-kappa Bp65, and RNA polymerase II to the CD40 promoter and enhanced histone 4 acetylation in a time-dependent manner. Thus, our results have elucidated the molecular mechanisms underlying leptin-induced CD40 expression and DC maturation.