Abstract
Diverse cellular responses to external cues are controlled by a small number of signal-transduction pathways, but how the specificity of functional outcomes is achieved remains unclear. Here we describe a mechanism for signal integration based on the functional coupling of two distinct signaling pathways widely used in leukocytes: the ITAM pathway and the Jak-STAT pathway. Through the use of the receptor for interferon-γ (IFN-γR) and the ITAM adaptor Fcγ as an example, we found that IFN-γ modified responses of the phagocytic antibody receptor FcγRI (CD64) to specify cell-autonomous antimicrobial functions. Unexpectedly, we also found that in peritoneal macrophages, IFN-γR itself required tonic signaling from Fcγ through the kinase PI(3)K for the induction of a subset of IFN-γ-specific antimicrobial functions. Our findings may be generalizable to other ITAM and Jak-STAT signaling pathways and may help explain signal integration by those pathways.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacterial Load
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Cells, Cultured
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Immunoglobulin Fc Fragments / genetics
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Immunoglobulin Fc Fragments / metabolism
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Immunoreceptor Tyrosine-Based Activation Motif / genetics
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Immunoreceptor Tyrosine-Based Activation Motif / immunology*
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Interferon gamma Receptor
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Janus Kinase 2 / genetics
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Janus Kinase 2 / metabolism*
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Listeriosis / immunology*
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Macrophages / immunology*
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Mice
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Mice, Inbred Strains
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Mice, Knockout
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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Phagocytosis / genetics
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Phosphoinositide-3 Kinase Inhibitors
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Protein Engineering
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Receptor Cross-Talk / immunology*
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Receptors, IgG / genetics
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Receptors, IgG / metabolism
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Receptors, Interferon / metabolism
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Transcriptional Activation / drug effects
Substances
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Immunoglobulin Fc Fragments
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Phosphoinositide-3 Kinase Inhibitors
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Receptors, IgG
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Receptors, Interferon
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STAT1 Transcription Factor
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Interferon-gamma
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Jak2 protein, mouse
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Janus Kinase 2