Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice

Injury to the central nervous system (CNS) elicits an inflammatory response involving activation of microglia, brain macrophages, and astrocytes, proc esses likely mediated by the release of proinflammatory cytokines. In order to determine the role of interleukin-6 (IL-6) during the inflammatory resp onse in the brain following disruption of the blood-brain barrier (BBB), we examined the effects of a focal cryo injury to the fronto-parietal cortex in interleukin-6-deficient (IL-6-/-) and normal (IL-6+/+) mice. In IL-6+/mice, brain injury resulted in the appearance of brain macrophages and reac tive astrocytes surrounding the lesion site. In addition, expression of gra nulocyte-macrophage colony-stimulating factor (GM-CSF) and metallothionein- I + II (MT-I+II) were increased in these cells, while the brain-specific NI T-III was only moderately upregulated. In IL-6-/- mice, however, the respon se of brain macrophages and reactive astrocytes was markedly depressed and the number of NSE positive neurons was reduced. Brain damage-induced GM-CSF and MT-I+II expression were also markedly depressed compared to IL-6+/+ mi ce. In contrast, NIT-III immunoreactivity was markedly increased in brain m acrophages and astrocytes. In situ hybridization analysis indicates that MT -I+II but not MT-III immunoreactivity reflect changes in the messenger leve ls. The number of cell divisions was similar in IL-6+/+ and IL-6-/- mice. T he present results demonstrate that IL-6 is crucial for the recruitment of myelo-monocytes and activation of glial cells following brain injury with d isrupted BBB. Furthermore, our results suggest IL-6 is important for neurop rotection and the induction of GM-CSF and MT expression. The opposing effec t of IL-6 on MT-I+II and MT-III levels in the damaged brain suggests MT iso form-specific functions. (C) 1999 Wiley-Liss, Inc.