A mechanism underlying STAT4-mediated up-regulation of IFN-gamma induction inTCR-triggered T cells.
IL-12 promotes T(h)1 development/IFN-gamma expression by activating STAT4. However, it is still unclear how STAT4 elicits IFN-gamma promoter activation. Here, we investigated the mechanism by which IL-12-activated STAT4 functions for IFN-gamma induction in TCR-triggered T cells. TCR stimulation induced high levels of IFN-gamma production depending on co-stimulation with IL-12. IL-12 stimulation greatly enhanced the promoter-binding activity of c-Jun/AP-1, a critical transcription factor for IFN-gamma gene expression in wild-type T cells, but not in STAT4-deficient (STAT4(-/-)) T cells. Comparable amounts of c-Jun were induced by TCR stimulation in both wild-type and STAT4(-/-) T cells irrespective of IL-12 co-stimulation. However, c-Jun bound to STAT4 in IL-12-co-stimulated wild-type T cells. c-Jun forming a complex with STAT4 efficiently interacted with the AP-1-related sequence of the IFN-gamma promoter. Such an enhanced c-Jun binding did not occur in STAT4(-/-) T cells. These results show that STAT4 contributes to enhancing IFN-gamma expression by up-regulating the binding of TCR signal-induced AP-1 to the relevant promoter sequence.
Park
Woong-Ryeon
WR
Department of Oncology (C6), Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Nakahira
Masakiyo
M
Sugimoto
Naotoshi
N
Bian
Yang
Y
Yashiro-Ohtani
Yumi
Y
Zhou
Xu-Yu
XY
Yang
Yi-Fu
YF
Hamaoka
Toshiyuki
T
Fujiwara
Hiromi
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D016758:Genes, jun / Q000235:genetics / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000235:genetics; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D018417:Th1 Cells / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D004268:DNA-Binding Proteins; D011948:Receptors, Antigen, T-Cell; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D018664:Interleukin-12; D007371:Interferon-gamma