Critical role for cathepsin B in mediating caspase-1-dependent interleukin-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin

Cell Death Differ. 2003 Sep;10(9):956-68. doi: 10.1038/sj.cdd.4401264.


The potassium ionophore nigericin induces cell death and promotes the maturation and release of IL-1beta in lipopolysaccharide (LPS)-primed monocytes and macrophages, the latter depending on caspase-1 activation by an unknown mechanism. Here, we investigate the pathway that triggers cell death and activates caspase-1. We show that without LPS priming, nigericin alone triggered caspase-1 activation and IL-18 generation in THP-1 monocytic cells. Simultaneously, nigericin induced caspase-1-independent necrotic cell death, which was blocked by the cathepsin B inhibitor CA-074-Me and other cathepsin inhibitors. Cathepsin B activation after nigericin treatment was determined biochemically and corroborated by rapid lysosomal leakage and translocation of cathepsin B to the cytoplasm. IL-18 maturation was prevented by both caspase-1 and cathepsin B inhibitors in THP-1 cells, primary mouse macrophages and human blood monocytes. Moreover, IL-18 generation was reduced in THP-1 cells stably transformed either with cystatin A (an endogenous cathepsin inhibitor) or antisense cathepsin B cDNA. Collectively, our study establishes a critical role for cathepsin B in nigericin-induced caspase-1-dependent IL-18 maturation and caspase-1-independent necrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Toxins / antagonists & inhibitors
  • Bacterial Toxins / pharmacology*
  • Calpain / metabolism
  • Caspase 1 / metabolism*
  • Cathepsin B / antagonists & inhibitors
  • Cathepsin B / physiology*
  • Cell Line
  • Cells, Cultured
  • Cysteine Proteinase Inhibitors / pharmacology
  • Dipeptides / pharmacology
  • Interleukin-18 / biosynthesis
  • Interleukin-18 / metabolism*
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mice
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / enzymology
  • Monocytes / immunology*
  • Necrosis*
  • Nigericin / antagonists & inhibitors
  • Nigericin / pharmacology*
  • Protein Transport / drug effects


  • Bacterial Toxins
  • CA 074 methyl ester
  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • Interleukin-18
  • Lipopolysaccharides
  • Calpain
  • Cathepsin B
  • Caspase 1
  • Nigericin