Role of Caspase-1 in experimental pneumococcal meningitis: Evidence from pharmacologic Caspase inhibition and Caspase-1-deficient mice.
Caspase 1 plays a pivotal role in generating mature cytokine interleukin-1beta. Interleukin-1beta is implicated as a mediator of pneumococcal meningitis, both in experimental models and in humans. We demonstrated here that (1) Caspase 1 mRNA and protein expression is upregulated in the brain during experimental pneumococcal meningitis, and (2) Caspase 1 levels are elevated in the cerebrospinal fluid of patients with acute bacterial meningitis. The upregulation/activation of Caspase 1 was associated with increased levels of interleukin-1beta. Depletion of the Caspase 1 gene and pharmacologic blockade of Caspase 1 significantly attenuated the meningitis-induced increase in interleukin-1beta. This was paralleled by a significantly diminished inflammatory host response to pneumococci. The antiinflammatory effect of Caspase 1 depletion or blockade was associated with a marked reduction of meningitis-induced intracranial complications, thus leading to an improved clinical status. In humans, cerebrospinal fluid Caspase 1 levels correlated with the clinical outcome. Thus, pharmacologic inhibition may provide an efficient adjuvant therapeutic strategy in this disease.
Koedel
Uwe
U
Department of Neurology, Klinikum Grosshadern, Ludwig Maximilians-University, Munich, Germany.
Winkler
Frank
F
Angele
Barbara
B
Fontana
Adriano
A
Flavell
Richard A
RA
Pfister
Hans-Walter
HW
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D061945:Caspase Inhibitors; D002493:Central Nervous System Diseases / Q000382:microbiology; D002555:Cerebrospinal Fluid / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008586:Meningitis, Pneumococcal / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D051381:Rats; D015854:Up-Regulation
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007375:Interleukin-1; D008054:Lipid Peroxides; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020170:Caspase 1