Abstract
Initially described as an antiviral cytokine, IFN-alpha has been subsequently shown to affect several cellular functions, including cellular differentiation and proliferation. For these reasons, IFN-alpha is currently used in clinical practice for the treatment of viral infections and malignancies. In this manuscript, we show two novel mechanisms concomitantly responsible for the antiproliferative effect of IFN-alpha. First, long-term treatment with IFN-alpha of primary CD4+ T cells reduced surface expression of CD3 and CD28. These events resulted in decreased phosphorylation of the mitogen-activated extracellular signal-regulated activating kinase and its substrate extracellular signal-regulated kinase, leading to diminished production of IL-2. Second, IFN-alpha treatment of primary CD4+ T cells reduced proliferative response to stimulation in the presence of exogenous IL-2 by markedly decreasing mRNA synthesis and surface expression of CD25 (alpha-chain), a critical component of the IL-2R complex. These results may be relevant for the antitumor effects of IFN-alpha and may help us to better understand its detrimental role in the inhibition of proliferation of the bulk of CD4+ T cells (uninfected cells) in HIV-infected persons, who are known to overproduce IFN-alpha.
MeSH terms
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CD28 Antigens / biosynthesis
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CD28 Antigens / immunology
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CD3 Complex / biosynthesis
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CD3 Complex / immunology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / enzymology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism*
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Cell Membrane / drug effects
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Cells, Cultured
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Humans
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Immune Sera / pharmacology
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Interferon Type I / pharmacology*
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Interleukin-2 / antagonists & inhibitors*
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Interleukin-2 / biosynthesis*
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Interleukin-2 / physiology
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / metabolism
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RNA, Messenger / antagonists & inhibitors
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RNA, Messenger / biosynthesis
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Receptors, Interleukin-2 / antagonists & inhibitors*
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Receptors, Interleukin-2 / genetics
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Receptors, Interleukin-2 / physiology*
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Recombinant Proteins
Substances
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CD28 Antigens
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CD3 Complex
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Immune Sera
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Interferon Type I
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Interleukin-2
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RNA, Messenger
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Receptors, Interleukin-2
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Recombinant Proteins
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases