Proinflammatory
cytokines mediate
brain injury in experimental studies. This study was undertaken to analyze the production of proinflammatory
cytokines in experimental
contusion. A
brain contusion causing delayed
edema was mimicked experimentally in rats using a weight-drop model. Intracerebral expression of the
cytokines interleukin (IL)-1 beta,
tumor necrosis factor-alpha (
TNF alpha),
IL-6, and
interferon-gamma (IFN gamma) was studied by in situ hybridization and immunohistochemistry. The animals were killed at 6 hours or 1, 2, 4, 6, 8, or 16 days postinjury. In the injured area, no messenger (m)
RNA expression was seen during the first 2 days after the
trauma. On Days 4 to 6 posttrauma, however, strong
IL-1 beta,
TNF alpha, and
IL-6 mRNA expression was detected in mononuclear cells surrounding the
contusion. Expression of IFN gamma was not detected. Immunohistochemical double labeling confirmed the in situ hybridization results and demonstrated that mononuclear phagocytes and astrocytes produced
IL-1 beta and that mainly astrocytes produced
TNF alpha. The findings showed, somewhat unexpectedly, a late peak of intracerebral
cytokine production in the injured area and in the contralateral corpus callosum, allowing for both local and global effects on the brain. An unexpected difference in the cellular sources of
TNF alpha and
IL-1 beta was detected. The
cytokine pattern differs from that seen in other central nervous system inflammatory diseases and
trauma models, suggesting that the intracerebral immune response is not a uniform event. The dominance of late
cytokine production indicates that many
cytokine effects are late events in an experimental
contusion: Different pathogenic mechanisms may thus be operative at different times after
brain injury.