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Mast cell tumor necrosis factor α production is regulated by MEK kinases

By Tamotsu Ishizuka, Naohiro Terada, Pär Gerwins, Eckard Hamelmann, Akihiro Oshiba, Gary R. Fanger, Gary L. Johnson and Erwin W. Gelfand


Mast cells synthesize and secrete specific cytokines and chemokines which play an important role in allergic inflammation. Aggregation of the high-affinity Fc receptor (FcɛRI) for immunoglobulin E (IgE) in MC/9 mouse mast cells stimulates the synthesis and secretion of tumor necrosis factor α (TNF-α). FcɛRI aggregation activates several sequential protein kinase pathways, leading to increased activity of extracellular signal-regulated kinases (ERKs), c-Jun amino-terminal kinases (JNKs), and the p38 mitogen-activated protein (MAP) kinase. Inhibition of ERKs with the compound PD 098059 had little effect on FcɛRI-stimulated TNF-α production. Aggregation of FcɛRI stimulated MEK kinase 1 (MEKK1) activity, which activates JNK kinase (JNKK), the kinase that phosphorylates and activates JNKs. Expression of activated MEKK1 (ΔMEKK1) in MC/9 cells strongly stimulated JNK activity but only weakly stimulated p38 activity, and it induced a large activation of TNF-α promoter-regulated luciferase gene expression. Inhibitory mutant JNK2 expressed in MC/9 cells significantly blunted FcɛRI stimulation of TNF-α promoter-driven luciferase expression. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, diminished FcɛRI-mediated TNF-α synthesis, significantly blunted JNK activation and TNF-α promoter-driven luciferase expression, and only weakly inhibited p38 kinase activation. Inhibition of NFκB activation resulting from ΔMEKK1 expression or FcɛRI stimulation did not affect TNF-α promoter-driven luciferase expression. Our findings define a MEKK-regulated JNK pathway activated by FcɛRI that regulates TNF-α production in mast cells

Topics: Biological Sciences
Publisher: The National Academy of Sciences of the USA
Year: 1997
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Provided by: PubMed Central
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