Intravenous Granulocyte Colony‐Stimulating Factor Increases the Release of Tumour Necrosis Factor and Interleukin‐1β into the Cerebrospinal Fluid, But Does Not Inhibit the Growth of Streptococcus pneumoniae in Experimental Meningitis

Abstract

Granulocyte colony‐stimulating factor (G‐CSF) possesses an antimicrobial effect in several animal models of infection. To evaluate a possible effect of G‐CSF on the course of pneumococcal meningitis, rabbits infected intracisternally (i.c.) with Streptococcus pneumoniae type 3 (n = 7) received 50 μg/kg of rhG‐CSF intravenously (i.v.) 1 h prior to infection. Seven infected animals served as controls. Uninfected rabbits received 10 μg of G‐CSF (n = 3), 2 μg G‐CSF (n = 3) or saline (n = 3) i.c. G‐CSF injected i.c. did not produce cerebrospinal fluid (CSF) leucocytosis. Compared with the control group, i.v. G‐CSF given prior to i.c. infection increased the percentage of granulocytes in blood 6 h and 12 h after infection. Twelve hours after infection, CSF tumour necrosis factor (TNF) activity and CSF interleukin (IL)‐1β concentrations were significantly higher in G‐CSF‐treated animals. G‐CSF did not decrease bacterial growth in the subarachnoid space and the CSF leucocyte densities were not influenced. At 24 h after infection, G‐CSF did not reduce the CSF concentrations of neurone‐specific enolase and the density of apoptotic neurones in the dentate gyrus of the hippocampus. In conclusion, i.v. G‐CSF increased the concentration of pro‐inflammatory cytokines in the CSF but did not decrease the growth of Streptococcus pneumoniae in the subarachnoid space.

Characterization of a pneumococcal meningitis mouse model

“…This discrepancy may be explained by the lack of measurements that were performed between 6 and 30 hours after infection. IL-1β, which in humans is increased in the first 18 hours of infection [25], was also markedly increased in brain homogenates, but not in blood in our mice 30 hours after infection. The IL-6 concentrations did significantly increase CSF, brain homogenate and plasma 30 hours after infection.…”

Inflammasome activation mediates inflammation and outcome in humans and mice with pneumococcal meningitis

“…Moreover, mice deficient of caspase-1 displayed less severe inflammation, decreased brain water content and improved clinical score in a pneumococcal meningitis model [10,12]. Second, IL-1β, which is activated by caspase-1, has been shown to be elevated in the CSF of children with pneumococcal meningitis and correlates with disease severity [11], a finding that also has been observed in various animal models [13-15]. Lastly, several murine models have demonstrated the importance of NLRP3 in the pathophysiology of invasive pneumococcal disease [16,17].…”

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

“…CSF IL-1␤ levels are increased in the first 18 h of infection (438). Pro-IL-1␤ is cleaved into its active form by caspase-1, which is regulated by a group of different receptors called the inflammasome (408).…”

“…In mice with pneumococcal meningitis, expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the brain was increased (376). Rabbits pretreated with G-CSF intravenously 1 h before intrathecal inoculation with S. pneumoniae showed increased peripheral but not subarachnoid leukocytosis and increased CSF levels of TNF and IL-1 but no reduction of subarachnoid bacterial outgrowth or neuron-specific enolase, an indicator of neuronal cell damage (438). A similar experiment showed no influence on subarachnoid bacterial killing, but systemic pleocytosis and bacterial killing were increased (362).…”