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Ras and Mitogen-Activated Protein Kinase Kinase Kinase-1 Coregulate Activator Protein-1– and Nuclear Factor-B–Mediated Gene Expression in Airway Epithelial Cells

Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan; and Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois

Address correspondence to: Marc B. Hershenson, M.D., University of Michigan, 1500 E. Medical Center Dr., L2211 Women's Hospital, Box 0212, Ann Arbor, MI 48109-0212. E mail: mhershen{at}umich.edu

In 16HBE14o- human bronchial epithelial cells, maximal tumor necrosis factor (TNF)-–induced interleukin (IL)-8 expression depends on the activation of two distinct signaling pathways, one constituted in part by activator protein (AP)-1 and the other by nuclear factor (NF)-B. We examined the upstream signaling intermediates responsible for IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in this system, hypothesizing that p21 Ras and mitogen-activated protein kinase/extracellular signal–regulated kinase kinase kinase (MEKK)-1 function as common upstream activators of both the AP-1 and NF-B pathways. TNF- treatment induced both Ras and MEKK1 activation. Dominant-negative forms of Ras (N17Ras) and MEKK1 (MEKK1-KM) each inhibited TNF-–induced transcription from IL-8 and GM-CSF promoters. Ras was required for maximal activation of extracellular signal–regulated kinase (ERK) and Jun amino terminal kinase (JNK) as well as AP-1 and NF-B transcriptional activities, but not for activation of IB kinase (IKK)-ß, an upstream activator of NF-B. MEKK1 was required for maximal activation of ERK, JNK, and IKK, as well as for maximal AP-1 and NF-B transcriptional activities. We conclude that Ras regulates TNF-–induced chemokine expression by activating the AP-1 pathway and enhancing transcriptional function of NF-B, whereas MEKK1 activates both the AP-1 and NF-B pathways.

Abbreviations: activator protein-1, AP-1 • enzyme-linked immunosorbent assay, ELISA • extracellular signal regulated kinase, ERK • fetal bovine serum, FBS • granulocyte macrophage colony-stimulating factor, GM-CSF • hemagglutinin, HA • IB kinase, IKK • interleukin-8, IL-8 • mitogen-activated protein kinase, MAP kinase • MAP kinase/ERK kinase, MEK • MEK kinase, MEKK • minimum essential medium, MEM • nuclear factor-B, NF-B • NF-B–inducing kinase, NIK • tumor necrosis factor-, TNF-

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