Age-related effects of interleukin-1 beta on polymorphonuclear neutrophil-dependent increases in blood-brain barrier permeability in rats

Abstract

In adult rats, 50,000 units of recombinant interleukin-1 beta (IL-1 beta) injected into the brain parenchyma produced an intense meningitis and disruption of the blood-CSF barrier by 4 h. No increase in vascular permeability to horseradish peroxidase or leukocyte recruitment was observed at the site of injection. By contrast, in juvenile rats, 100 units of IL-1 beta injected into the striatum gave rise to a large increase in blood-brain barrier permeability and recruitment of polymorphonuclear neutrophils into the tissue around the injection site by 4 h. This effect was also accompanied by a marked meningitis. The injection of 100 units of IL-1 beta into neonatal (2-h-old) rats gave rise to an increase in permeability of vessels to serum proteins in the meninges, but no increase in vascular permeability was observed at the injection site. The IL-1 beta-induced increases in vessel permeability in the meninges, parenchyma, and choroid plexus were polymorphonuclear neutrophil dependent, since leukocyte depletion by irradiation or polymorphonuclear neutrophil anti-serum pre-treatment eliminated the response in the juvenile animals and in the adults. Seventy-five thousand units of murine tumour necrosis factor-alpha injected into the parenchyma of both adults and juvenile animals failed to induce an increase in blood-brain barrier permeability or polymorphonuclear neutrophil recruitment, but did give rise to a mild meningitis. These findings demonstrate clear differences in the responsiveness of different CNS compartments to IL-1 beta. Furthermore, while tumour necrosis factor-alpha and IL-1 beta might have been expected to exhibit similar proinflammatory effects in the CNS, this is not the case. We also show, for the first time, that age has a significant effect on the response to a cytokine. The "window of susceptibility' to an inflammatory stimulus in juvenile rats, if paralleled in humans, may be a major factor in the increased susceptibility of children to trauma or to infectious insults to the CNS.