Uncoupling of promitogenic and antiapoptotic functions of IL-2 by Smad-dependent TGF-beta signaling.
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.
Nelson
Brad H
BH
Benaroya Research Institute, Seattle, WA 98101, USA. bnelson@bccancer.bc.ca
Martyak
Timothy P
TP
Thompson
Lucas J
LJ
Moon
James J
JJ
Wang
Tongwen
T
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology; D017930:Genes, Reporter / Q000276:immunology; D006131:Growth Inhibitors / Q000502:physiology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008894:Milk Proteins; D008934:Mitogens / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid / Q000276:immunology; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051785:Smad Proteins; D051900:Smad3 Protein; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D018909:src Homology Domains / Q000235:genetics / Q000276:immunology
D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D007376:Interleukin-2; D008894:Milk Proteins; D008934:Mitogens; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D051785:Smad Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta