Cutting edge: IL-12 and IL-18 differentially regulate the transcriptional activity of the human IFN-γ promoter in primary CD4+ T lymphocytes

K Barbulescu, C Becker, JF Schlaak… - The Journal of …, 1998 - journals.aai.org
K Barbulescu, C Becker, JF Schlaak, E Schmitt, KH Meyer zum Büschenfelde, MF Neurath
The Journal of Immunology, 1998journals.aai.org
We analyzed the molecular mechanisms by which IL-12 and IL-18 induce transcriptional
activity of the IFN-γ promoter in primary human CD4+ T cells. In transfection experiments, we
found that IL-18 directly induces IFN-γ promoter activity, whereas significant activation with
IL-12 required costimulation with αCD3/CD28. Furthermore, IL-12 caused in vivo protection
of a STAT4 (− 236) binding site, whereas stimulation with IL-18 or IL-12 plus αCD3/CD28
induced occupancy of a downstream AP-1 site. Mutation of this AP-1 site abrogated both IL …
Abstract
We analyzed the molecular mechanisms by which IL-12 and IL-18 induce transcriptional activity of the IFN-γ promoter in primary human CD4+ T cells. In transfection experiments, we found that IL-18 directly induces IFN-γ promoter activity, whereas significant activation with IL-12 required costimulation with αCD3/CD28. Furthermore, IL-12 caused in vivo protection of a STAT4 (− 236) binding site, whereas stimulation with IL-18 or IL-12 plus αCD3/CD28 induced occupancy of a downstream AP-1 site. Mutation of this AP-1 site abrogated both IL-12-and IL-18-mediated promoter activation, whereas mutation of the STAT site inhibited IL-12-dependent activation. These data suggest that both AP-1 and STAT4 are required for IL-12-dependent IFN-γ promoter activity, whereas IL-18 causes direct activation via AP-1. This differential activation of the IFN-γ promoter gives further insights into molecular pathways governing Th1 T cell development and differentiation.
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