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Overproduction of proinflammatory cytokines in the brains of transgenic animals causes brain pathology. To investigate the relationship between brain cytokines and pathology in the brains of animals with adult-onset, pathophysiologically induced brain cytokine expression, we studied rats infected with 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-1beta and tumor necrosis factor-alpha in the brains of the animals. Similar spatiotemporal inductions of mRNAs for inhibitory factor kappaBalpha and interleukin-1beta converting enzyme were found and quantified. The mRNAs for inducible nitric oxide synthase and interleukin-1 receptor antagonist were highly localized to the choroid plexus, which showed evidence of structural abnormalities associated with the parasites' presence there. The mRNAs for interleukin-6, interferon-gamma, and inducible cyclooxygenase showed restricted induction patterns. Another set of animals was processed for degeneration-induced silver staining, TdT-mediated dUTP-digoxigenin nick end-labeling (TUNEL) staining, glial fibrillary acidic protein (GFAP) immunohistochemistry, and several other histological markers. Apoptosis of scattered small cells and degeneration of certain nerve fibers was found in patterns spatially related to the cytokine mRNA patterns and to cerebrospinal fluid diffusion pathways. Furthermore, striking cytoarchitectonically defined clusters of degenerating non-neuronal cells, probably astrocytes, were found. The results reveal chronic overexpression of potentially cytotoxic cytokines in the brain and selective histopathology patterns in this natural disease model. J. Comp. Neurol. 414:114-130, 1999. Published 1999 Wiley-Liss, Inc.

Systemically administered lipopolysaccharide (LPS) elicits profound changes in pituitary hormone secretion. Pro-inflammatory cytokines have been proposed as mediators of these responses. In this study, we used in-situ hybridization histochemistry to investigate LPS-induced cytokine gene expression in the rat pituitary. After i.p. or i.v. injection of various doses of LPS, mRNA for the immediate-early gene IkappaBu (an inhibitor of NF-kappaB, a transcription factor that regulates the expression of many pro-inflammatory cytokines) was induced in the anterior lobe as early as 0.5 h. The induced IkappaBalpha mRNA expression peaked at 1 h. In the posterior lobe, IkappaBalpha mRNA was first induced at 0.5 h and peaked at 2 h. A similar spatiotemporal pattern of interleukin-1b (IL-1) mRNA induction was observed. In addition, at 2 h after injection, TNFalpha, IL-1beta converting enzyme (ICE), and IL-1 receptor antagonist (IL-1RA) mRNAs were induced in both anterior and posterior lobes. Type 1 IL-1 receptor (IL-1R1) mRNA was constitutively expressed in the pituitary, and its expression level did not change after the LPS injection. Interestingly, the mRNA coding for glial fibrillary acidic protein (GFAP), an astrocyte marker, was selectively induced in the posterior lobe at 2 h after LPS injection, suggesting that LPS affects pituicyte function. Together, these results suggest that LPS acts directly on the pituitary to rapidly induce cytokine expression. Locally synthesized cytokines may activate cytokine receptor bearing cells to modulate the endocrine activities of the pituitary.