Granulocyte-Macrophage Colony-Stimulating Factor in the Innate Immune Response to Pneumocystis carinii Pneumonia in Mice

• Published in: The Journal of immunology (1950) Vol. 164; no. 5; pp. 2602 - 2609
• Main Authors: Paine, Robert, III, Preston, Angela M, Wilcoxen, Steven, Jin, Hong, Siu, Brian B, Morris, Susan B, Reed, Jacquelyn A, Ross, Gary, Whitsett, Jeffrey A, Beck, James M
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01-03-2000
• Subjects: Animals; Cells, Cultured; Genetic Predisposition to Disease; Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis; Granulocyte-Macrophage Colony-Stimulating Factor - deficiency; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - physiology; Immunity, Innate - genetics; innate immunity; Lung - immunology; Lung - metabolism; Lung - microbiology; Lung - pathology; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Macrophages, Alveolar - microbiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Phagocytosis - genetics; Phagocytosis - immunology; Pneumocystis - immunology; Pneumocystis carinii; Pneumonia, Pneumocystis - genetics; Pneumonia, Pneumocystis - immunology; Pneumonia, Pneumocystis - metabolism; Pneumonia, Pneumocystis - pathology; Proteolipids - genetics; Pulmonary Surfactants - genetics; Pulmonary Surfactants - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.164.5.2602

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.