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¹ The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
² Department of Immunology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
³ Department of Genome Sciences, Faculty of Meducal Sciences, Graduate School of Medicine, Kobe University, Kobe, Japan

STAT4 is a critical mediator of IL-12-stimulated gene regulation in T-helper type 1 (Th1) cell. IL-12 activates the Janus family tyrosine kinases JAK2 and Tyk2, which in turn phosphorylate STAT4 on tyrosine 693. The p38 mitogen-activated protein kinase (MAPK) signaling pathway is also activated in response to IL-12, followed by phosphorylation of STAT4 on serine 721, which is required for STAT4 full transcriptional activity. In the present study, we demonstrated constitutive activation of STAT4 in HTLV-I-transformed T-cell lines MT-2, MT-4 and HUT102 by immunoprecipitation, Western blotting and electrophoretic mobility shift assay (EMSA). In HTLV-I-transformed T-cell lines, STAT4 was constitutively phosphorylated not only on tyrosine 693 but also on serine 721, and formed a heterodimer with STAT3. Constitutive phosphorylation of its upstream activators, JAK2, Tyk2 and p38 MAPK was also observed in the cells. EMSA and transient transfection studies further showed that the high-affinity sis-inducible element (hSIE) preferentially binds the STAT3/STAT4 heterodimer and is constitutively transactivated in MT-2 cells in the absence of exogenous cytokine stimulation. When STAT4 expression vector was cotransfected along with STAT3 expression vector into MT-2 cells, STAT4 significantly synergized with STAT3 to transactivate hSIE, showing the functional importance of heterodimer formation between STAT4 and STAT3.

^* Correspondence: E-mail: jtsukada{at}med.uoeh-u.ac.jp