Akt-dependent cytokine production in mast cells

Cross-linking of Fc epsilon RI induces the activation of three protein tyro sine kinases, Lyn, Syk, and Bruton's tyrosine kinase (Btk), leading to the secretion of a panel of proinflammatory mediators from mast cells. This stu dy showed phosphorylation at Ser-473 and enzymatic activation of Akt/protei n kinase B, the crucial survival kinase, upon Fc epsilon RI stimulation in mouse mast cells. Phosphorylation of Akt is regulated positively by Btk and Syk and negatively by Lyn. Akt in turn can regulate positively the transcr iptional activity of interleukin (IL)-2 and tumor necrosis factor (TNF)-alp ha promoters. Transcription front the nuclear factor kappa B (NF-kappa\B), nuclear factor of activated T cells (NF-AT), and activator protein 1 (AP-1) sites within these promoters is under the control of Akt activity. Accordi ngly, the signaling pathway involving I kappa B-alpha, a cytoplasmic protei n that binds NF-kappa B and inhibits its nuclear translocation, appears to be regulated by Akt in mast cells. Catalytic activity of glycogen synthase kinase (GSK)-3 beta, a serine/threonine kinase that phosphorylates NF-AT an d promotes its nuclear export, seems to be inhibited by Akt. Importantly, A kt regulates the production and secretion of IL-2 and TNF-alpha in Fc epsil on RI-stimulated mast cells. Altogether, these results revealed a novel fun ction of Akt in transcriptional activation of cytokine genes via NF-kappa B , NF-AT, and AP-1 that contributes to the production of cytokines.