title: Legionella pneumophila evades gamma interferon-mediated growth suppression through interleukin-10 induction in bone marrow-derived macrophages.
abstract: We examined the roles of Th1-Th2 cytokine cross talk in Legionella 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-gamma) 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-gamma were detected in the culture supernatants of infected macrophages stimulated with IL-12 and IL-18 in combination but not independently. Neutralization of IFN-gamma by antibody completely abolished the growth inhibitory effects of IL-12 and IL-18. Interestingly, higher infectivity ratios of L. pneumophila or the addition of increasing concentrations of heat-killed bacteria (HKB) suppressed the production of IFN-gamma, which resulted in the increased intracellular growth of bacteria. Significant amounts of IL-10 were detected in culture supernatants when Legionella-infected macrophages were cocultured with HKB. Furthermore, neutralization of IL-10 by antibody resulted in an increase in IFN-gamma 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 of L. pneumophila. These findings demonstrate a crucial role of Th1-Th2 cross talk in L. pneumophila-infected BM macrophages. Our results also suggest that L. pneumophila modulates the cytokine balance from IFN-gamma-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 in Legionella-infected macrophages but also into the pathogenesis of L. pneumophila pneumonia in humans.
authors.affiliation: Department of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Ohmorinishi, Ohtaku, Tokyo 143-8540, Japan. kazu@med.toho-u.ac.jp
authors.forename: Sadako
authors.initials: S
authors.lastname: Yoshizawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tateda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Fumio
authors.initials: F
authors.lastname: Gondaira
authors.forename: Shuichi
authors.initials: S
authors.lastname: Miyazaki
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
authors.forename: Keizo
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis*; D016952:Legionella pneumophila / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D016753:Interleukin-10; D007371:Interferon-gamma