Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4

doi:10.1084/jem.181.5.1755

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Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4

NG Jacobson, SJ Szabo, RM Weber-Nordt, Z Zhong, RD Schreiber, JE Darnell Jr and KM Murphy
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Interleukin 12 (IL-12) initiates the differentiation of naive CD4+ T cells to T helper type 1 (Th1) cells critical for resistance to intracellular pathogens such as Leishmania major. To explore the basis of IL-12 action, we analyzed induction of nuclear factors in Th1 cells. IL-12 selectively induced nuclear DNA-binding complexes that contained Stat3 and Stat4, recently cloned members of the family of signal transducers and activators of transcription (STATs). While Stat3 participates in signaling for several other cytokines, Stat4 was not previously known to participate in the signaling pathway for any natural ligand. The selective activation of Stat4 provides a basis for unique actions of IL-12 on Th1 development. Thus, this study presents the first identification of the early events in IL-12 signaling in T cells and of ligand activation of Stat4.
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Ostrand-Rosenberg, S., Grusby, M. J., Clements, V. K. (2000). Cutting Edge: STAT6-Deficient Mice Have Enhanced Tumor Immunity to Primary and Metastatic Mammary Carcinoma. J. Immunol. 165: 6015-6019 [Abstract] [Full Text]
Zhu, J., Huang, H., Guo, L., Stonehouse, T., Watson, C. J., Hu-Li, J., Paul, W. E. (2000). Transient Inhibition of Interleukin 4 Signaling by T Cell Receptor Ligation. JEM 192: 1125-1134 [Abstract] [Full Text]
Murphy, T. L., Geissal, E. D., Farrar, J. D., Murphy, K. M. (2000). Role of the Stat4 N Domain in Receptor Proximal Tyrosine Phosphorylation. Mol. Cell. Biol. 20: 7121-7131 [Abstract] [Full Text]
Gollob, J. A., Veenstra, K. G., Jyonouchi, H., Kelly, A. M., Ferrieri, P., Panka, D. J., Altare, F., Fieschi, C., Casanova, J.-L., Frank, D. A., Mier, J. W. (2000). Impairment of STAT Activation by IL-12 in a Patient with Atypical Mycobacterial and Staphylococcal Infections. J. Immunol. 165: 4120-4126 [Abstract] [Full Text]
Visconti, R., Gadina, M., Chiariello, M., Chen, E. H., Stancato, L. F., Gutkind, J. S., O'Shea, J. J. (2000). Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood 96: 1844-1852 [Abstract] [Full Text]
Carson, W. E., Dierksheide, J. E., Jabbour, S., Anghelina, M., Bouchard, P., Ku, G., Yu, H., Baumann, H., Shah, M. H., Cooper, M. A., Durbin, J., Caligiuri, M. A. (2000). Coadministration of interleukin-18 and interleukin-12 induces a fatal inflammatory response in mice: critical role of natural killer cell interferon-gamma production and STAT-mediated signal transduction. Blood 96: 1465-1473 [Abstract] [Full Text]
Kalina, U., Kauschat, D., Koyama, N., Nuernberger, H., Ballas, K., Koschmieder, S., Bug, G., Hofmann, W.-K., Hoelzer, D., Ottmann, O. G. (2000). IL-18 Activates STAT3 in the Natural Killer Cell Line 92, Augments Cytotoxic Activity, and Mediates IFN-{gamma} Production by the Stress Kinase p38 and by the Extracellular Regulated Kinases p44erk-1 and p42erk-21. J. Immunol. 165: 1307-1313 [Abstract] [Full Text]
Zhang, S., Kaplan, M. H. (2000). The p38 Mitogen-Activated Protein Kinase Is Required for IL-12-Induced IFN-{gamma} Expression. J. Immunol. 165: 1374-1380 [Abstract] [Full Text]
Glimcher, L. H., Murphy, K. M. (2000). Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev. 14: 1693-1711 [Full Text]
Kitani, A., Fuss, I. J., Nakamura, K., Schwartz, O. M., Usui, T., Strober, W. (2000). Treatment of Experimental (Trinitrobenzene Sulfonic Acid) Colitis by Intranasal Administration of Transforming Growth Factor (TGF)-{beta}1 Plasmid: TGF-{beta}1-mediated Suppression of T Helper Cell Type 1 Response Occurs by Interleukin (IL)-10 Induction and IL-12 Receptor {beta}2 Chain Downregulation. JEM 192: 41-52 [Abstract] [Full Text]
Frucht, D. M., Aringer, M., Galon, J., Danning, C., Brown, M., Fan, S., Centola, M., Wu, C.-Y., Yamada, N., El Gabalawy, H., O'Shea, J. J. (2000). Stat4 Is Expressed in Activated Peripheral Blood Monocytes, Dendritic Cells, and Macrophages at Sites of Th1-Mediated Inflammation. J. Immunol. 164: 4659-4664 [Abstract] [Full Text]
Durbin, J. E., Fernandez-Sesma, A., Lee, C.-K., Rao, T. D., Frey, A. B., Moran, T. M., Vukmanovic, S., Garcia-Sastre, A., Levy, D. E. (2000). Type I IFN Modulates Innate and Specific Antiviral Immunity. J. Immunol. 164: 4220-4228 [Abstract] [Full Text]
Heath, V. L., Showe, L., Crain, C., Barrat, F. J., Trinchieri, G., O'Garra, A. (2000). Cutting Edge: Ectopic Expression of the IL-12 Receptor-{beta}2 in Developing and Committed Th2 Cells Does Not Affect the Production of IL-4 or Induce the Production of IFN-{gamma}. J. Immunol. 164: 2861-2865 [Abstract] [Full Text]
Yin, Z., Zhang, D.-H., Welte, T., Bahtiyar, G., Jung, S., Liu, L., Fu, X.-Y., Ray, A., Craft, J. (2000). Dominance of IL-12 Over IL-4 in {gamma}{delta} T Cell Differentiation Leads to Default Production of IFN-{gamma}: Failure to Down-Regulate IL-12 Receptor {beta}2-Chain Expression. J. Immunol. 164: 3056-3064 [Abstract] [Full Text]