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

Publisher Website
Google Scholar
Abstract
The proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNFalpha) 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-1beta and TNFalpha on inflammatory response, cell death, and edema development. Intracerebral microinjections of these cytokines were administered to rats. The animals were killed 24 or 72 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-1beta 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 Bax, and 69.6+/-4.6% of the TUNEL-positive cells expressed the antiapoptotic gene Bcl-2; the Bax expression was stronger than the Bcl-2 expression. Taken together, the data indicate that cell death occurred via the apoptotic pathway. The TNFalpha did not induce inflammation or DNA fragmentation within the analyzed time period. Both IL-1beta (p < 0.001) and TNFalpha (p < 0.01) caused vasogenic edema, as measured by specific gravity and albumin staining. The edematous effect of TNFalpha persisted 72 hours after injection (p < 0.01), whereas the IL-1beta-treated animals had normalized by that time. Intracerebral inflammation, death of intrinsic CNS cells, and vasogenic edema can be mediated by IL-1beta, and TNFalpha can cause vasogenic edema. Suppression of these cytokines in the clinical setting may improve outcome.
Keywords