TNF-α, inducible NO synthase (iNOS), and ICAM-1 are considered to be key proteins in the inflammatory response of most tissues. We tested the hypothesis that cell walls of Streptococcus pneumoniae (PCW), the most common cause of adult bacterial meningitis, induce TNF-α, iNOS, and ICAM-1 expression in rat primary brain microvascular endothelial cell cultures. We detected TNF-α mRNA by RT-PCR already 1 h after stimulation with PCW, while TNF-α protein peaked at 4 h (9.4±3.6 vs 0.1±0.1 pg/μg protein). PCW induced iNOS mRNA 2 h after stimulation, followed by an increase of the NO degradation product nitrite (18.1±4 vs 5.8±1.8 at 12 h; 18.1±4 vs 5.8±1.8 pmol/μg protein at 72 h). The addition of TNF-α Ab significantly reduced nitrite production to 62.2±14.4% compared with PCW-stimulated brain microvascular endothelial cells (100%). PCW induced the expression of ICAM-1 (measured by FACS), which was completely blocked by TNF-α Ab (142±18.6 vs 97.5±12.4%; 100% unstimulated brain microvascular endothelial cells). Cerebral endothelial cells express TNF-α mRNA as well as iNOS mRNA and release the bioactive proteins in response to PCW. PCW-induced NO production is mediated in part by an autocrine pathway involving TNF-α, whereas ICAM-1 expression is completely mediated by this autocrine loop. By these mechanisms, cerebral endothelial cells may regulate critical steps in inflammatory blood-brain-barrier disruption of bacterial meningitis.