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Maher 2014 J Biol Chem

From Bioblast
Publications in the MiPMap
Maher K, Jerič Kokelj B, Butinar M, Mikhaylov G, Manček-Keber M, Stoka V, Vasiljeva O, Turk B, Grigoryev SA, Kopitar-Jerala N (2014) A role for stefin B (cystatin B) in inflammation and endotoxemia. J Biol Chem 289:31736-50.

» PMID: 25288807 Open Access

Maher K, Jeric Kokelj B, Butinar M, Mikhaylov G, Mancek-Keber M, Stoka V, Vasiljeva O, Turk B, Grigoryev SA, Kopitar-Jerala N (2014) J Biol Chem

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.

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Keywords: Caspase, Inflammasome, Mitochondria, Reactive Oxygen Species (ROS), Sepsis


Labels: Pathology: Neurodegenerative  Stress:Oxidative stress;RONS  Organism: Mouse