DELAYED CYTOKINE EXPRESSION IN RAT-BRAIN FOLLOWING EXPERIMENTAL CONTUSION

Proinflammatory cytokines mediate brain injury in experimental studies . This study was undertaken to analyze the production of proinflammato ry cytokines in experimental contusion. A brain contusion causing dela yed edema was mimicked experimentally in rats using a weight-drop mode l. Intracerebral expression of the cytokines interleukin (IL)-1 beta, tumor necrosis factor-alpha (TNF alpha), IL-6, and interferon-gamma (I FN gamma) was studied by in situ hybridization and immunohistochemistr y. The animals were killed at 6 hours or 1, 2, 4, 6, 8, or 16 days pos tinjury. 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, h owever, strong IL-1 beta, TNF alpha, and IL-6 mRNA expression was dete cted 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 p hagocytes and astrocytes produced IL-1 beta and that mainly astrocytes produced TNF alpha. The findings showed, somewhat unexpectedly, a lat e 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 source s of TNF alpha and IL-1 beta was detected. The cytokine pattern differ s 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 indi cates that many cytokine effects are late events in an experimental co ntusion. Different pathogenic mechanisms may thus be operative at diff erent times after brain injury.