Intracerebral administration of interleukin-1 beta and induction of inflammation, apoptosis, and vasogenic edema

Object. The proinflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF alpha) are produced intracerebrally in brain disorders such as trauma, ischemia, meningitis, and multiple sclerosis. This investigation was undertaken to analyze the effect of intracerebral administration of IL-1 beta and TNF alpha on inflammatory response, cell death, and edema development. Methods. Intracerebral microinjections of these cytokines were administered to rats. The animals were killed 24 or 71 hours after the injections, and their brains were analyzed by using deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) with digoxigenin-labeled deoxyuridine triphosphate, immunohistochemical studies, and brain-specific gravity measurement. The IL-1 beta induced a transient inflammatory response (p < 0.001) and TUNEL staining (p < 0.001), indicating cell death, in intrinsic central nervous system (CNS) cells and infiltrating inflammatory cells. In 73.8 +/- 6.77% of the TUNEL-positive cells, small, fragmented nuclei were found. All TUNEL-positive cells expressed the proapoptotic gene Box, and 69.6 +/- 4.6% of thr TUNEL-positive cells expressed the antiapoptotic gene Bcl-2, the Bar expression was stronger than the Bcl-2 expression. Taken together, the data indicate that cell death occurred via the apoptotic pathway. The TNF alpha did not induce inflammation or DNA fragmentation within the analyzed time peri od. Both IL-1 beta (p < 0.001) and TNF alpha (p < 0.01) caused vasogenic edema, as measured by specific gravity and albumin staining. The edematous effect of TNF alpha persisted 72 hours after injection (p < 0.01), whereas the IL-1 beta-treated animals had normalized by that time. Conclusions. lntracerebral inflammation, death of intrinsic CNS cells, and vasogenic edema can be mediated by IL-1 beta, and TNF alpha can cause vasogenic edema. Suppression of these cytokines in the clinical setting may improve outcome.