title: Granulocyte-macrophage colony-stimulating factor in the innate immune response to Pneumocystis carinii pneumonia in mice.
abstract: Innate immunity plays an important role in pulmonary host defense against Pneumocystis carinii, an important pathogen in individuals with impaired cell-mediated immunity. We investigated the role of GM-CSF in host defense in a model of P. carinii pneumonia induced by intratracheal inoculation of CD4-depleted mice. Lung GM-CSF levels increased progressively during the infection and were significantly greater than those in uninfected controls 3, 4, and 5 wk after inoculation. When GM-CSF gene-targeted mice (GM-/-) depleted of CD4+ cells were inoculated with P. carinii, the intensities of infection and inflammation were increased significantly compared with those in CD4-depleted wild-type mice. In contrast, transgenic expression of GM-CSF directed solely in the lungs of GM-/- mice (using the surfactant protein C promoter) dramatically decreased the intensity of infection and inflammation 4 wk after inoculation. The concentrations of surfactant proteins A and D were greater in both uninfected and infected GM-/- mice compared with those in wild-type controls, suggesting that this component of the innate response was preserved in the GM-/- mice. However, alveolar macrophages (AM) from GM-/- mice demonstrated impaired phagocytosis of purified murine P. carinii organisms in vitro compared with AM from wild-type mice. Similarly, AM production of TNF-alpha in response to P. carinii in vitro was totally absent in AM from GM-/- mice, while GM-CSF-replete mice produced abundant TNF in this setting. Thus, GM-CSF plays a critical role in the inflammatory response to P. carinii in the setting of impaired cell-mediated immunity through effects on AM activation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Michigan, and Department of Veterans Affairs Medical Center, Ann Arbor, MI 48105, USA. rpaine@umich.edu
authors.forename: R
authors.initials: R
authors.lastname: Paine
authors.forename: A M
authors.initials: AM
authors.lastname: Preston
authors.forename: S
authors.initials: S
authors.lastname: Wilcoxen
authors.forename: H
authors.initials: H
authors.lastname: Jin
authors.forename: B B
authors.initials: BB
authors.lastname: Siu
authors.forename: S B
authors.initials: SB
authors.lastname: Morris
authors.forename: J A
authors.initials: JA
authors.lastname: Reed
authors.forename: G
authors.initials: G
authors.lastname: Ross
authors.forename: J A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: J M
authors.initials: JM
authors.lastname: Beck
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007113:Immunity, Innate / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D011010:Pneumocystis / Q000276:immunology; D011020:Pneumonia, Pneumocystis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011510:Proteolipids / Q000235:genetics; D011663:Pulmonary Surfactants / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D011510:Proteolipids; D011663:Pulmonary Surfactants; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor