PRODUCTION OF FUNCTIONAL IL-18 BY DIFFERENT SUBTYPES OF MURINE AND HUMAN DENDRITIC CELLS (DC) - DC-DERIVED IL-18 ENHANCES IL-12-DEPENDENT TH1 DEVELOPMENT

IL-18 is a recently described cytokine that shares biological activiti es with IL-12 in driving the development of Th1-type T cells. As dendr itic cells (DC) are very potent inducers of T cell proliferation and d ifferentiation we wondered whether they utilize IL-18 as a factor driv ing Th1 development. We demonstrate by Northern blot and reverse trans cription-PCR that various subtypes of human and murine DC as well as t he DC-line XS contain IL-18 mRNA. When supernatants of either enriched Langerhans cells (LC) or bone marrow-derived DC were analyzed for pro duction of IL-18 protein, IL-18 production was detected in an IL-18-sp ecific ELISA. To assess whether the IL-18 protein released by DC is fu nctional, we performed a sensitive bioassay using the IL-18-dependent stimulation of concanavalin A-stimulated T cells. Both, supernatants f rom bone marrow-derived DC and enriched LC induced IFN-gamma productio n in the T cells. This production was partially inhibitable by additio n of anti-IL-18 antiserum. In a TCR-transgenic mouse system we further demonstrate that DC-derived IL-18 potentiates IL-12-dependent Th1 dev elopment. Using DC derived from IL-12 knockout animals, we show that D C-derived IL-18 by itself is not capable of inducing Th1 cell differen tiation. Together the data demonstrate that subtypes of DC are able to release functional IL-18 that is able to induce IFN-gamma production and Th1 differentiation in primed T cells.