GRANULOCYTE-COLONY-STIMULATING FACTOR WORSENS THE OUTCOME OF EXPERIMENTAL KLEBSIELLA-PNEUMONIAE PNEUMONIA THROUGH DIRECT INTERACTION WITH THE BACTERIA

Besides its well-established effects on granulocytopoiesis, granulocyt e colony-stimulating factor (G-CSF) has been shown to have direct effe cts on the recruitment and bactericidal ability of neutrophils, result ing in improved survival of experimentally infected animals. We studie d the effect of G-CSF on the course of experimental pneumonia induced by Klebsiella pneumoniae, an important gram-negative bacillary pulmona ry pathogen. Using a highly reproducible murine model, we here show th e paradoxical finding that mortality from infection was significantly increased when animals received G-CSF before induction of pneumonia. A dministration of G-CSF promoted replication of bacteria in the river a nd 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 i n the lung, liver, and spleen, and abrogated the increased mortality c aused by G-CSF. In vitro studies showed a direct effect of G-CSF on K pneumoniae resulting in increased capsular polysaccharide (CPS) produc tion. When bacteria were coincubated with therapeutically achievable c oncentrations of G-CSF, phagocytic uptake and killing by neutrophils w as impaired. Western blot analysis showed three binding sites of G-CSF to K pneumoniae. Binding of I-125-G-CSF to K pneumoniae was displaced by an excess of unlabeled G-CSF, whereas an unrelated cytokine, inter leukin-1 alpha, did not compete with G-CSF binding to the bacteria. Th us, 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. (C) 1998 by The American So ciety of Hematology.