TCR and IL-12 receptor signals cooperate to activate an individual response element in the IFN-gamma promoter in effector Th cells.
IFN-gamma is a key regulatory cytokine of the immune system. Reporter transgenic mice expressing the luciferase gene under the control of separate TCR-response elements (TCR-RE) from the IFN-gamma promoter or expressing the green fluorescent protein gene under the control of an IFN-gamma "minigene" were employed to explore the basis for IL-12 regulation of IFN-gamma gene transcription. In the absence of TCR stimulation, IL-12 did not activate the TCR-REs but did induce green fluorescent protein expression. TCR plus IL-12R stimulation of effector Th cells resulted in: 1) enhanced activation of the proximal, but not the distal, TCR-RE, and 2) increased induction of cJun-proximal TCR-RE complexes and c-Jun protein expression. Overexpression of cJun, but not cFos, increased activity of the proximal TCR-RE in T cells. These results suggest that IL-12R signaling affects IFN-gamma gene transcription by at least two separate mechanisms; IL-12R signaling without TCR signaling targets promoter regions outside of the approximately 100-bp IFN-gamma TCR-RE, and IL-12R signaling also stimulates TCR-induced activity of the proximal TCR-RE.
Division of Rheumatology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
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Nakamura
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Aune
D000818:Animals; D017252:CD3 Complex / Q000276:immunology; D002478:Cells, Cultured; D007106:Immune Sera / Q000494:pharmacology; D007108:Immune Tolerance / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics*; D018664:Interleukin-12 / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008934:Mitogens / Q000494:pharmacology; D009687:Nuclear Proteins / Q000096:biosynthesis; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology*; D018123:Receptors, Interleukin / Q000502:physiology*; D053707:Receptors, Interleukin-12; D020218:Response Elements / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism*
D017252:CD3 Complex; D007106:Immune Sera; D008934:Mitogens; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D007371:Interferon-gamma