Abstract
Engagement of the IFN-alphabeta receptor initiates multiple signaling cascades, including activation of the STAT. In this study, we demonstrate that IFN-alphabeta, although antiproliferative in wild-type CD4(+) or CD8(+) T cells, act as strong mitogens on their STAT1(-/-) counterparts. Furthermore, IFN-alphabeta exert little effect on apoptosis in wild-type cells, but are potent survival factors in the absence of STAT1. The antiapoptotic response in the absence of STAT1 is predominantly mediated by STAT3, and to a lesser extent by STAT5A/B. In contrast, the mitogenic IFN-alphabeta response gained through the absence of STAT1 is only marginally affected when STAT5A/B expression is also abrogated, but is completely dependent on STAT3 activation. These findings provide the first evidence for a function of STAT3 and STAT5A/B in the IFN-alphabeta response, and support a model in which the IFN-alphabeta receptor initiates both pro- and antiapoptotic responses through STAT1, and STAT3 and STAT5A/B, respectively.
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / immunology
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Cell Proliferation
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Cell Survival / immunology
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Cells, Cultured
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Growth Inhibitors / pharmacology
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Growth Inhibitors / physiology
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Interferon Type I / pharmacology
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Interferon Type I / physiology*
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Interferon-alpha / physiology
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Interferon-beta / pharmacology
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Interferon-beta / physiology
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Lymphocyte Activation / genetics
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Mice
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Mice, Knockout
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Milk Proteins / genetics
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Mitogens / pharmacology
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Mitogens / physiology
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Resting Phase, Cell Cycle / genetics
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Resting Phase, Cell Cycle / immunology
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism*
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Trans-Activators / physiology*
Substances
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DNA-Binding Proteins
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Growth Inhibitors
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Interferon Type I
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Interferon-alpha
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Milk Proteins
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Mitogens
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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Stat1 protein, mouse
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Stat3 protein, mouse
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Stat5a protein, mouse
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Trans-Activators
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Interferon-beta