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  • 1
    Online Resource
    Online Resource
    Critical Role for STAT4 Activation by Type 1 Interferons in the Interferon-γ Response to Viral Infection
    American Association for the Advancement of Science (AAAS) ; 2002
    In:  Science Vol. 297, No. 5589 ( 2002-09-20), p. 2063-2066
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 297, No. 5589 ( 2002-09-20), p. 2063-2066
    Abstract: Interferons (IFNs) are essential for host defense. Although the antiviral effects of the type 1 IFNs IFN-α and IFN-β (IFN-α/β) have been established, their immunoregulatory functions, especially their ability to regulate IFN-γ production, are poorly understood. Here we show that IFN-α/β activate STAT4 directly (STAT, signal transducers and activators of transcription) and that this is required for IFN-γ production during viral infections of mice, in concert with T cell receptor–derived signals. In contrast, STAT1 appears to negatively regulate IFN-α/β induction of IFN-γ. Thus, type 1 IFNs, in addition to interleukin-12, provide pathways for innate regulation of adaptive immunity, and their immunoregulatory functions are controlled by modulating the activity of individual STATs.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1074900
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2002
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    detail.hit.zdb_id: 2060783-0
    SSG: 11
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    STAT4 serine phosphorylation is critical for IL-12-induced IFN-γ production but not for cell proliferation
    Proceedings of the National Academy of Sciences ; 2002
    In:  Proceedings of the National Academy of Sciences Vol. 99, No. 19 ( 2002-09-17), p. 12281-12286
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 99, No. 19 ( 2002-09-17), p. 12281-12286
    Abstract: T helper 1 (T H 1) differentiation and IFN-γ production are crucial in cell-mediated immune responses. IL-12 is an important regulator of this process and mediates its effects through signal transducer and activator of transcription 4 (STAT4). IFN-γ production is also regulated by the p38 mitogen-activated kinase pathway, although the mechanisms are ill-defined. We show here that GADD45-β and GADD45-γ can induce STAT4 S721 phosphorylation via the MKK6/p38 pathway. Thus, STAT4 could be a target that accounts for the defects in cell-mediated immunity associated with perturbations in the p38 pathway. To investigate the biological significance of STAT4 S721 phosphorylation, we reconstituted primary spleen cells from STAT4-deficient mice with wild-type and mutated STAT4, by using a retroviral gene transduction. We demonstrated that expression of wild-type STAT4, but not the S721A mutant, restored normal T H 1 differentiation and IFN-γ synthesis. The inability of STAT4 S721 to restore IFN-γ production was not caused by decreased IL-12R expression because the STAT4 S721 mutant also failed to restore IFN-γ production in STAT4-deficient IL-12Rβ2 transgenic cells. Importantly, STAT4 S721A-transduced cells showed normal proliferative response to IL-12, illustrating that serine phosphorylation is not required for IL-12-induced proliferation. Additionally, the results imply the existence of STAT4 serine phosphorylation-dependent and -independent target genes. We conclude that phosphorylation of STAT4 on both tyrosine and serine residues is important in promoting normal T H 1 differentiation and IFN-γ secretion.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.182618999
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2002
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    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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