Chronic overexpression of proinflammatory cytokines and histopathology in the brains of rats infected with Trypanosoma brucei

Overproduction of proinflammatory cytokines in the brains of transgenic ani mals causes brain pathology. To investigate the relationship between brain cytokines and pathology in the brains of animals with adult-onset, pathophy siologically induced brain cytokine expression, we studied rats infected wi th the parasite Trypanosoma brucei. Several weeks after infection, in situ hybridization histochemistry showed a pattern of chronic overexpression of the mRNAs for proinflammatory cytokines interleukin-1 beta and tumor necros is factor-alpha in the brains of the animals. Similar spatiotemporal induct ions of mRNAs for inhibitory factor kappa B alpha and interleukin-1 beta co nverting enzyme were found and quantified. The mRNAs for inducible nitric o xide synthase and interleukin-1 receptor antagonist were highly localized t o the choroid plexus, which showed evidence of structural abnormalities ass ociated with the parasites' presence there. The mRNAs for interleukin-6, in terferon-gamma, and inducible cyclooxygenase showed restricted induction pa tterns. Another set; of animals was processed for degeneration-induced silv er staining, TdT-mediated dUTP-digoxigenin nick end-labeling (TUNEL) staini ng, glial fibrillary acidic protein (GFAP) immunohistochemistry, and severa l other histological markers. Apoptosis of scattered small cells and degene ration of certain nerve fibers was found in patterns spatially related to t he cytokine mRNA patterns and to cerebrospinal fluid diffusion pathways. Fu rthermore, striking cytoarchitectonically defined clusters of degenerating non-neuronal cells, probably astrocytes, were found. The results reveal chr onic overexpression of potentially cytotoxic cytokines in the brain and sel ective histopathology patterns in this natural disease model. (C) Published 1999 Wiley-Liss, Inc.