Akt-dependent Cytokine Production in Mast Cells

doi:10.1084/jem.192.5.729

Published online 5 September 2000.

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© The Rockefeller University Press, 0022-1007/2000/9/729/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 5, September 5, 2000 729-740

Original Article

Akt-dependent Cytokine Production in Mast Cells

Jiro Kitaura^a, Koichi Asai^a, Mari Maeda-Yamamoto^b, Yuko Kawakami^a, Ushio Kikkawa^c, and Toshiaki Kawakami^a
^a Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121
^b National Research Institute of Vegetables, Ornamental Plants, and Tea, Shizuoka 428-8501, Japan
^c Biosignal Research Center, Kobe University, Kobe 657-8501, Japan

Correspondence to: Toshiaki Kawakami, Division of Allergy, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121. Tel:858-558-3500 Fax:858-558-3526 E-mail:toshi_kawakami{at}liai.org.

Cross-linking of Fc ${epsilon}$ RI induces the activation of three proteintyrosine kinases, Lyn, Syk, and Bruton's tyrosine kinase (Btk),leading to the secretion of a panel of proinflammatory mediatorsfrom mast cells. This study showed phosphorylation at Ser-473and enzymatic activation of Akt/protein kinase B, the crucialsurvival kinase, upon Fc ${epsilon}$ RI stimulation in mouse mast cells.Phosphorylation of Akt is regulated positively by Btk and Sykand negatively by Lyn. Akt in turn can regulate positively thetranscriptional activity of interleukin (IL)-2 and tumor necrosisfactor (TNF)- ${alpha}$ promoters. Transcription from the nuclear factor ${kappa}$ B (NF- ${kappa}$ B), nuclear factor of activated T cells (NF-AT), and activatorprotein 1 (AP-1) sites within these promoters is under the controlof Akt activity. Accordingly, the signaling pathway involvingI ${kappa}$ B- ${alpha}$ , a cytoplasmic protein that binds NF- ${kappa}$ B and inhibits itsnuclear translocation, appears to be regulated by Akt in mastcells. Catalytic activity of glycogen synthase kinase (GSK)-3ß,a serine/threonine kinase that phosphorylates NF-AT and promotesits nuclear export, seems to be inhibited by Akt. Importantly,Akt regulates the production and secretion of IL-2 and TNF- ${alpha}$ in Fc ${epsilon}$ RI-stimulated mast cells. Altogether, these results revealeda novel function of Akt in transcriptional activation of cytokinegenes via NF- ${kappa}$ B, NF-AT, and AP-1 that contributes to the productionof cytokines.

Key Words: Fc ${epsilon}$ RI, Lyn, Btk, NF- ${kappa}$ B, signal transduction

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