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

Katarina Maher, Barbara Jerič Kokelj, Miha Butinar, Georgy Mikhaylov, Mateja Manček-Keber, Veronika Stoka, Olga Vasiljeva, Boris Turk, Sergei A. Grigoryev, Natasa Kopitar-Jerala

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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 proinflammatory cytokines IL-1ß 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-lß processing. Pretreatment of macrophages with the cathepsin inhibitor E-64d did not affect secretion of IL-lß, 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.

Original languageEnglish (US)
Pages (from-to)31736-31750
Number of pages15
JournalJournal of Biological Chemistry
Volume289
Issue number46
DOIs
StatePublished - Nov 14 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'A role for stefin B (cystatin B) in inflammation and endotoxemia'. Together they form a unique fingerprint.

Cite this