Caspase 1 deficiency reduces inflammation-induced brain transcription.
The systemic inflammatory response syndrome (SIRS) is a life-threatening medical condition characterized by a severe and generalized inflammatory state that can lead to multiple organ failure and shock. The CNS regulates many features of SIRS such as fever, cardiovascular, and neuroendocrine responses. Central and systemic manifestations of SIRS can be induced by LPS or IL-1beta administration. The crucial role of IL-1beta in inflammation has been further highlighted by studies of mice lacking caspase 1 (casp1, also known as IL-1beta convertase), a protease that cleaves pro-IL-1beta into mature IL-1beta. Indeed, casp1 knockout (casp1(-/-)) mice survive lethal doses of LPS. The key role of IL-1beta in sickness behavior and its de novo expression in the CNS during inflammation led us to test the hypothesis that IL-1beta plays a major role modulating the brain transcriptome during SIRS. We show a gene-environment effect caused by LPS administration in casp1(-/-) mice. During SIRS, the expression of several genes, such as chemokines, GTPases, the metalloprotease ADAMTS1, IL-1RA, the inducible nitric oxide synthase, and cyclooxygenase-2, was differentially increased in casp1(-/-) mice. Our findings may contribute to the understanding of the molecular changes that take place within the CNS during sepsis and SIRS and the development of new therapies for these serious conditions. Our results indicate that those genes may also play a role in several neuropsychiatric conditions in which inflammation has been implicated and indicate that casp1 might be a potential therapeutic target for such disorders.
Mastronardi
Claudio
C
Center on Pharmacogenomics, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Whelan
Fiona
F
Yildiz
Ozlem A
OA
Hannestad
Jonas
J
Elashoff
David
D
McCann
Samuel M
SM
Licinio
Julio
J
Wong
Ma-Li
ML
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D020170:Caspase 1 / Q000172:deficiency*; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D018746:Systemic Inflammatory Response Syndrome; D014158:Transcription, Genetic / Q000187:drug effects
D008070:Lipopolysaccharides; D020170:Caspase 1