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

J Biol Chem. 2014 Nov 14;289(46):31736-31750. doi: 10.1074/jbc.M114.609396. Epub 2014 Oct 6.


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.

Keywords: Caspase; Inflammasome; Mitochondria; Reactive Oxygen Species (ROS); Sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspases / metabolism
  • Caspases, Initiator
  • Cystatin B / physiology*
  • Endotoxemia / metabolism*
  • Escherichia coli / metabolism
  • Gene Expression Regulation*
  • Inflammasomes / metabolism
  • Inflammation / metabolism*
  • Lipopolysaccharides
  • Macrophages / cytology
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondria / metabolism
  • NF-kappa B / metabolism
  • Reactive Oxygen Species / metabolism


  • Cstb protein, mouse
  • Inflammasomes
  • Lipopolysaccharides
  • NF-kappa B
  • Reactive Oxygen Species
  • Cystatin B
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator