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Granulocyte Colony-Stimulating Factor Worsens the Outcome of
Experimental Klebsiella pneumoniae Pneumonia Through Direct
Interaction With the Bacteria
Thomas K. Held,
Martin E.A. Mielke,
Marcio Chedid,
Matthias Unger,
Matthias Trautmann,
Dieter Huhn, and
Alan S. Cross
From the Department of Hematology and Oncology and the Department of
Paidopathology und Placentology, Virchow-Klinikum, Humboldt-University;
the Institute for Infectious Diseases, Department of Medical
Microbiology and Infectious Diseases Immunology, Free University,
Berlin, Germany; the Laboratory of Cellular and Molecular Biology,
National Cancer Institute, National Institutes of Health, Bethesda, MD;
the Department of Microbiology, University of Ulm, Germany; and the
Division of Infectious Diseases and Program in Oncology, University of
Maryland Medical School, Baltimore, MD.
Besides its well-established effects on granulocytopoiesis,
granulocyte colony-stimulating factor (G-CSF) has been shown to have
direct effects on the recruitment and bactericidal ability of
neutrophils, resulting in improved survival of experimentally infected
animals. We studied the effect of G-CSF on the course of experimental
pneumonia induced by Klebsiella pneumoniae, an important
gram-negative bacillary pulmonary pathogen. Using a highly reproducible
murine model, we here show the paradoxical finding that mortality from
infection was significantly increased when animals received G-CSF
before induction of pneumonia. Administration of G-CSF promoted
replication of bacteria in the liver and spleen, thus indicating an
impairment rather than an enhancement of antibacterial mechanisms. By
contrast, a monoclonal antibody against Klebsiella K2 capsule
significantly reduced bacterial multiplication in the lung, liver, and
spleen, and abrogated the increased mortality caused by G-CSF. In vitro
studies showed a direct effect of G-CSF on K pneumoniae
resulting in increased capsular polysaccharide (CPS) production. When
bacteria were coincubated with therapeutically achievable
concentrations of G-CSF, phagocytic uptake and killing by neutrophils
was impaired. Western blot analysis showed three binding sites of G-CSF
to K pneumoniae. Binding of 125I-G-CSF to K
pneumoniae was displaced by an excess of unlabeled G-CSF, whereas
an unrelated cytokine, interleukin-1 , did not compete with G-CSF
binding to the bacteria. Thus, in this model, the direct effect of
G-CSF on a bacterial virulence factor, CPS production, outweighed any
beneficial effect of G-CSF on recruitment and stimulation of
leukocytes.
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2525-2535
© 1998 by The American Society of Hematology.
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