Expression and alternative processing of IL-18 in human neutrophils

Eur J Immunol. 2006 Mar;36(3):722-31. doi: 10.1002/eji.200535402.


Interleukin-18 (IL-18), a member of the IL-1 cytokine superfamily, is an important regulator of both innate and acquired immune responses. We demonstrate here constitutive expression of IL-18 by human neutrophils. Unexpectedly, we observed that neutrophils from peripheral blood or rheumatoid synovial compartments contained not only pro and mature IL-18, but also several novel smaller-molecular-weight IL-18-derived species. Using specific protease inhibitors, and serine protease gene-targeted mice, we demonstrate that these IL-18-derived products arose through caspase-independent cleavage events mediated by the serine proteases, elastase and cathepsin G. Moreover, we report that the net effect of elastase treatment of mature recombinant IL-18 was to reduce its IFN-gamma-inducing activity. Thus, human neutrophils contain IL-18 and IL-18-derived molecular species that can arise through novel enzymatic processing pathways. Through cytosolic, membrane or secretory expression of such processing enzymes, together with generation of IL-18 itself, neutrophils likely play a critical role in regulating IL-18 activities during early innate immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Humans
  • Immunity, Innate / immunology*
  • Interferon-gamma / immunology
  • Interleukin-18 / immunology*
  • Mice
  • Mice, Knockout
  • Neutrophil Activation / genetics
  • Neutrophil Activation / immunology*
  • Neutrophils / enzymology
  • Neutrophils / immunology*
  • Peptide Hydrolases / deficiency
  • Peptide Hydrolases / immunology
  • Protein Processing, Post-Translational / immunology*
  • Secretory Vesicles / enzymology
  • Secretory Vesicles / immunology*


  • Interleukin-18
  • Interferon-gamma
  • Peptide Hydrolases