title: IL-12 selectively regulates STAT4 via phosphatidylinositol 3-kinase and Ras-independent signal transduction pathways.
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.
authors.affiliation: Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London, GB.
authors.forename: V
authors.initials: V
authors.lastname: Athié-M
authors.forename: H
authors.initials: H
authors.lastname: Flotow
authors.forename: K L
authors.initials: KL
authors.lastname: Hilyard
authors.forename: D A
authors.initials: DA
authors.lastname: Cantrell
mesh_terms: D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000276:immunology*; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000276:immunology*; D018631:ras Proteins / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D018664:Interleukin-12; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins