Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 17, Pages 7205-7210Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0701366104
Keywords
IL-1 beta; LPS; mouse
Categories
Funding
- NCRR NIH HHS [RR 017365, K24 RR017365, K24 RR016996-06, K12 RR017611, RR 017611, K24 RR016996, RR 016996] Funding Source: Medline
- NHGRI NIH HHS [R03 HG002500, HG 002500] Funding Source: Medline
- NHLBI NIH HHS [K30 HL004526, HL 004526] Funding Source: Medline
- NIDDK NIH HHS [DK 063240, R01 DK063240, R01 DK058851, DK 058851] Funding Source: Medline
- NIGMS NIH HHS [U01 GM061394, GM 061394-04] Funding Source: Medline
- NIMH NIH HHS [MH 062777] Funding Source: Medline
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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 LIPS or IL-1 beta administration. The crucial role of IL-1 beta in inflammation has been further highlighted by studies of mice lacking caspase 1 (casp1, also known as IL-1 beta convertase), a protease that cleaves pro-IL-1 beta into mature IL-1 beta. Indeed, casp1 knockout (casp1(-/-)) mice survive lethal doses of LPS. The key role of IL-1 beta in sickness behavior and its de novo, expression in the CNS during inflammation led us to test the hypothesis that IL-1 beta 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.
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