| First Author | Maher K | Year | 2014 |
| Journal | J Biol Chem | Volume | 289 |
| Issue | 46 | Pages | 31736-31750 |
| PubMed ID | 25288807 | Mgi Jnum | J:315868 |
| Mgi Id | MGI:6832322 | Doi | 10.1074/jbc.M114.609396 |
| Citation | Maher K, et al. (2014) A role for stefin B (cystatin B) in inflammation and endotoxemia. J Biol Chem 289(46):31736-31750 |
| abstractText | 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-1beta 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-1beta processing. Pretreatment of macrophages with the cathepsin inhibitor E-64d did not affect secretion of IL-1beta, 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. |
