Abstract
TGF-beta opposes proliferative signaling by IL-2 through mechanisms that remain incompletely defined. In a well-characterized CD8(+) T cell model using wild-type and mutated IL-2 receptors, we examined the effects of TGF-beta on distinct IL-2 signaling events in CD8(+) T cells. IL-2 induces c-myc, cyclin D2, and cyclin E in a redundant manner through the Shc and STAT5 pathways. TGF-beta inhibited the ability of either the Shc or STAT5 pathway to induce these genes, as well as T cell proliferation. The inhibitory effects of TGF-beta were reversed by expression of a dominant-negative form of Smad3. TGF-beta did not impair proximal signaling by Shc or STAT5, and induction of some downstream genes, including cytokine-inducible Src homology-2-containing protein (CIS), bcl-x(L), and bcl-2, was spared. Experiments with c-fos, cyclin D2, and CIS reporter genes revealed that promoter-proximal regulatory elements dictate the sensitivity of IL-2 target genes to inhibition by TGF-beta. By leaving the Shc and STAT5 pathways functional while inhibiting their target genes selectively, TGF-beta was found to uncouple the proliferative and antiapoptotic functions of IL-2. Thus, TGF-beta is not a simple antagonist of IL-2, but rather serves to qualitatively modify the IL-2 signal to create a unique pattern of gene expression that neither cytokine can induce independently.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / immunology*
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Cell Division / immunology
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Cell Line
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Cell Survival / immunology
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / physiology*
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Gene Expression Regulation / immunology
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Genes, Reporter / immunology
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Growth Inhibitors / physiology
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / physiology*
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Mice
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Milk Proteins*
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Mitogens / antagonists & inhibitors
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Mitogens / genetics
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Mitogens / physiology*
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Promoter Regions, Genetic / immunology
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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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Regulatory Sequences, Nucleic Acid / immunology
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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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Smad Proteins
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Smad3 Protein
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / physiology*
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Transforming Growth Factor beta / physiology*
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src Homology Domains / genetics
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src Homology Domains / immunology
Substances
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DNA-Binding Proteins
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Growth Inhibitors
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Interleukin-2
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Milk Proteins
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Mitogens
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Receptors, Interleukin-2
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STAT5 Transcription Factor
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Smad Proteins
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Smad3 Protein
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Smad3 protein, mouse
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Trans-Activators
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Transforming Growth Factor beta