IL-12 selectively regulates STAT4 via phosphatidylinositol 3-kinase and Ras-independent signal transduction pathways

Verónica Athié-M., Horst Flotow, Katherine L. Hilyard, Doreen A. Cantrell (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    22 Citations (Scopus)

    Abstract

    IL-12 is an important immunomodulatory cytokine that induces tyrosine phosphorylation and activation of the signal transducer and activator of transcription (STAT)4. IL-12 induces sustained activation and nuclear translocation of STAT4 and this regulatory process is coupled to both tyrosine and serine phosphorylation of this molecule. IL-12-activated tyrosine kinases are the Janus kinases Jak2 and Tyk2 but little is known about IL-12 regulation of serine kinases. The object of the present study was to explore the role of mitogen-activated protein kinases (MAPK) Erk1 and Erk2 and phosphatidylinositol 3-kinase (PI3K) in STAT4 regulation. Here we show that the IL-12-induced STAT4 serine kinase is not sensitive to inhibitors of the PI3K or MAPK Erk1,2. Moreover, IL-12 activation of STAT4 in human peripheral blood-derived T cells is not accompanied by stimulation of the Ras guanine nucleotide binding cycle or stimulation of MAPK Erk1,2 or initiation of the PI3K signaling pathways. IL-12 is unable to initiate the serine phosphorylation of STAT 1 and 3. This reveals that the STAT1, 3 and 4 serine kinases are not coordinately regulated in human T cells and that IL-12 must regulate serine phosphorylation of STAT4 by a kinase network distinct to the MAPK Erk1,2 or PI3K pathways.

    Original languageEnglish
    Pages (from-to)1425-1434
    Number of pages10
    JournalEuropean Journal of Immunology
    Volume30
    Issue number5
    DOIs
    Publication statusPublished - 5 Jun 2000

    Keywords

    • IL-12
    • Mitogen-activated protein kinase
    • Phosphatidyl inositol 3-kinase
    • STAT4
    • T lymphocyte

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