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in IL-6- and IL-2-Mediated Cell Activation1
*
Tokyo University of Pharmacy and Life Science, Tokyo, Japan; and
Department of Biological Sciences, Wayne State University, Detroit, MI 48202
Many stimuli cause intracellular concentration oscillations of
second messengers or metabolites, which, in turn, may encode
information in their amplitudes and frequencies. We now test the
hypothesis that synergistic cellular responses to dual cytokine
exposure correlate with cross-talk between metabolic signaling pathways
of leukocytes. Polarized RAW264.7 macrophages and human neutrophils and
monocytes exhibited NAD(P)H autofluorescence oscillation periods of
20 s. IFN-
tripled the NAD(P)H oscillatory amplitude for these
cells. Although IL-6 had no effect, incubation of cells with IFN-
and IL-6 increased both oscillatory amplitude and frequency. Parallel
changes were noted after treatment with IFN- and IL-2. However,
IL-1ß and TNF-
did not display frequency doubling with or without
IFN- exposure. To determine whether frequency doubling required
complete IFN- signaling or simply metabolic amplitude modulation, an
electric field was applied to cells at NAD(P)H troughs, which has been
shown to enhance NAD(P)H amplitudes. Electric field application led to
frequency doubling in the presence of IL-6 or IL-2 alone, suggesting
that amplitude modulation is crucial to synergism. Because NADPH
participates in electron trafficking to NO, we tested NO production
during cytokine exposure. Although IL-6 and IL-2 alone had no effect,
IFN- plus IL-6 and IFN- plus IL-2 enhanced NO release in
comparison to IFN- treatment alone. When NO production was examined
for single cells, it incrementally increased with the same phase and
period as NAD(P)H. We suggest that amplitude and frequency modulation
of cellular metabolic oscillations contribute to intracellular
signaling synergy and entrain NO production.
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