ABSTRACTWe examined the roles of Th1-Th2 cytokine cross talk inLegionella pneumophila-infected bone marrow-derived (BM) macrophages in the presence of costimulation with interleukin-12 (IL-12) and IL-18. Treatment with gamma interferon (IFN-γ) alone or treatment with IL-12 in combination with IL-18 resulted in a 3- or 2-log reduction in bacterial numbers, respectively, in BM macrophages, whereas treatment with IL-12 or IL-18 alone had no effect. Significant amounts of IFN-γ were detected in the culture supernatants of infected macrophages stimulated with IL-12 and IL-18 in combination but not independently. Neutralization of IFN-γ by antibody completely abolished the growth inhibitory effects of IL-12 and IL-18. Interestingly, higher infectivity ratios ofL. pneumophilaor the addition of increasing concentrations of heat-killed bacteria (HKB) suppressed the production of IFN-γ, which resulted in the increased intracellular growth of bacteria. Significant amounts of IL-10 were detected in culture supernatants whenLegionella-infected macrophages were cocultured with HKB. Furthermore, neutralization of IL-10 by antibody resulted in an increase in IFN-γ production by infected BM macrophages when cocultured with HKB. Treatment of HKB with trypsin but not polymyxin B attenuated the growth-promoting effects of HKB, suggesting the involvement of a protein component(s) in regulation of the growth ofL. pneumophila. These findings demonstrate a crucial role of Th1-Th2 cross talk inL. pneumophila-infected BM macrophages. Our results also suggest thatL. pneumophilamodulates the cytokine balance from IFN-γ-driven Th1 to more Th2 responses, likely through the induction of IL-10 by a bacterial protein component(s). These data provide new insights not only into the cellular mechanisms of Th1-Th2 cross talk inLegionella-infected macrophages but also into the pathogenesis ofL. pneumophilapneumonia in humans.