A role for stefin B (cystatin B) in inflammation and endotoxemia.

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.

• 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)
• 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

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)