Transcriptional regulation of caspases in experimental pneumococcal meningitis

Apoptosis and necrosis in brain account for neurological sequelae in surviv ors of bacterial meningitis. In meningitis, several mechanisms may trigger death pathways leading to activation of transcription factors regulating ca spases mRNA synthesis. Therefore, we used a multiprobe RNA protection assay (RPA) to examine the expression of 9 caspase-6-mRNA in the course of exper imental Streptococcus pneumoniae meningitis in mouse brain. Caspase-6, -7 a nd -11 mRNA were elevated 6 hours after infection. 12 hours after infection caspases-1, -2, -8 and 12 mRNA rose. Caspase-14 mRNA was elevated 18 h and caspase-3 mRNA 24 h after infection. In situ hybridization detected caspas es-3, -8, -11 and -12 mRNA in neurons of the hippocampal formation and neoc ortex. Development of sepsis was paralleled by increased transcription of c aspases mRNA in the spleen. In TNF alpha -deficient mice all caspases examined were less upregulated, i n TNF-receptor 1/2 knockout mice caspases-1, -2, -7, -11 and -14 mRNA were increased compared to infected control animals. In caspase-1 deficient mice , caspases-11, and -12 mRNA levels did not rise in meningitis indicating th e necessity of caspase-1 activating these caspases. Hippocampal formations of newborn mice incubated with heat-inactivated S. pneumoniae R6 showed upr egulation of caspase-1, -3, -11 and -12 mRNA. These observations suggest a tightly regulated caspases network at the tran scriptional level in addition to the known cascade at the protein level.