Abstract |
Stefin B ( cystatin B) is an endogenous cysteine cathepsin inhibitor, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht-Lundborg disease (EPM1). In this study we demonstrated that stefin B-deficient (StB KO) mice were significantly more sensitive to the lethal LPS-induced sepsis and secreted higher amounts of pro-inflammatory cytokines IL-1β and IL-18 in the serum. We further showed that increased caspase-11 gene expression and better pro-inflammatory caspase-1 and -11 activation determined in StB KO bone marrow-derived macrophages resulted in enhanced IL-1β processing. Pretreatment of macrophages with the cathepsin inhibitor E-64d did not affect secretion of IL-1β, suggesting that the increased cathepsin activity determined in StB KO bone marrow-derived macrophages is not essential for inflammasome activation. Upon LPS stimulation, stefin B was targeted into the mitochondria, and the lack of stefin B resulted in the increased destabilization of mitochondrial membrane potential and mitochondrial superoxide generation. Collectively, our study demonstrates that the LPS-induced sepsis in StB KO mice is dependent on caspase-11 and mitochondrial reactive oxygen species but is not associated with the lysosomal destabilization and increased cathepsin activity in the cytosol.
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Authors | Katarina Maher, Barbara Jerič Kokelj, Miha Butinar, Georgy Mikhaylov, Mateja Manček-Keber, Veronika Stoka, Olga Vasiljeva, Boris Turk, Sergei A Grigoryev, Nataša Kopitar-Jerala |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 289
Issue 46
Pg. 31736-31750
(Nov 14 2014)
ISSN: 1083-351X [Electronic] United States |
PMID | 25288807
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. |
Chemical References |
- Cstb protein, mouse
- Inflammasomes
- Lipopolysaccharides
- NF-kappa B
- Reactive Oxygen Species
- Cystatin B
- Casp4 protein, mouse
- Caspases
- Caspases, Initiator
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Topics |
- Animals
- Caspases
(metabolism)
- Caspases, Initiator
- Cystatin B
(physiology)
- Endotoxemia
(metabolism)
- Escherichia coli
(metabolism)
- Gene Expression Regulation
- Inflammasomes
(metabolism)
- Inflammation
(metabolism)
- Lipopolysaccharides
- Macrophages
(cytology, metabolism)
- Mice
- Mice, Knockout
- Mice, Transgenic
- Mitochondria
(metabolism)
- NF-kappa B
(metabolism)
- Reactive Oxygen Species
(metabolism)
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