Proinflammatory cytokine expression contributes to brain injury provoked by chronic monocyte activation

Background: We have proposed that an increased interaction between monocyte /macrophages and blood vessel endothelium predisposes subjects to strokes. The effect of chronic monocyte activation on the development of cerebral in farcts was thus studied in rats after provocation of a modified local Swart zman reaction, in brain vasculature. Materials and Methods: Two weeks after an IV bolus of bacillus Calmette-Gue rin (BCG), we studied spontaneous superoxide production, integrin expressio n, endothelial adhesion of monocytes' and the neurological symptoms, brain histology, and cytokine immunoreactivity after a provocative dose of LPS (3 0-300 mug/rat i.c.v.). Results: Monocyte migration into the brain was stimulated by BCG priming. T he incidence of paralysis and death in response to LPS was markedly increas ed in BCG-primed rats. Histological evaluation of the brains of neurologica lly impaired and moribund animals revealed intravascular thrombosis and pal e and hemorrhagic infarcts. Infiltrates of leukocytes expressing immunoreac tive IL-1 beta, IL-6, and TNF-alpha were found around blood vessels, cerebr al ventricles, and meninges, and were accompanied by a profound microglial expression of IL1 beta, endothelial expression of IL-6, and expression of T NF-alpha and TNF-R1 in glia and neurons of cortex and hippocampus. Treatmen t (2 x 100 mug/10 mul, i.c.v.) with recombinant human (rh-)TNF 55kDa recept or completely prevented, and treatment with rh-IL-l receptor antagonist sig nificantly decreased the incidence of paralysis and death in response to BC G + LPS. The improvement of neurological symptoms was accompanied by reduce d histological damage and supppression of IL-1 beta expression in the brain tissue. Conclusions: The data demonstrate that chronic monocyte activation predispo ses subjects to thrombosis and hemorrhage via an exaggerated release of pro inflammatory cytokines.