Stat1 and Stat2 but not Stat3 arbitrate contradictory growth signals elicited by alpha/beta interferon in T lymphocytes.
Alpha/beta interferon (IFN-alpha/beta) triggers antiviral and antiproliferative responses in target cells through modulation of gene expression. The JAK-STAT pathway is the major mediator of these biological effects through the activation of the transcription factors STAT1 and STAT2, and gene ablation studies have demonstrated that both STAT1 and STAT2 are required for most antiviral responses induced by IFN-alpha/beta. However, additional signaling pathways are also activated by IFN. Here, we show that these additional pathways provoke a proliferative response in activated T lymphocytes. While activation of IFN-stimulated gene factor 3 produces a dominant inhibitory signal capable of overriding the mitogenic response, absence of either STAT1 or STAT2 leads to a proliferative response to IFN. Growth stimulation by IFN-alpha/beta is independent of other STAT proteins, particularly of STAT3, since T lymphocytes from STAT1-STAT3 double-knockout mice are growth stimulated by IFN-alpha/beta treatment. IFN-alpha/beta can cooperate with numerous T-cell mitogens, including interleukin-2 (IL-2), IL-4, IL-7, and IL-12, and can contribute to the rapid restoration of the thymus following glucocorticoid-mediated ablation. These results underscore the complexity of the cellular response to IFN and suggest that the ultimate outcome of IFN action results from a balance between growth-inhibitory and -stimulatory effects.
Gimeno
Ramon
R
Department of Pathology and Microbiology, 550 First Ave. MSB548, New York University School of Medicine, New York, New York 10016, USA.
Lee
Chien-Kuo
CK
Schindler
Christian
C
Levy
David E
DE
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011506:Proteins / Q000032:analysis; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D007376:Interleukin-2; D011506:Proteins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016899:Interferon-beta