Open AccessGranzymes A and K differentially potentiate LPS-induced cytokine response
Author(s) -
Annette C. Wensink,
Helena M. Kok,
Jan Meeldijk,
Job Fermie,
Christopher J. Froelich,
C. E. Hack,
Niels Bovenschen
Publication year - 2016
Publication title -
cell death discovery
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.556
H-Index - 28
ISSN - 2058-7716
DOI - 10.1038/cddiscovery.2016.84
Subject(s) - granzyme , tlr4 , cd14 , microbiology and biotechnology , cytotoxic t cell , toll like receptor , lipopolysaccharide , proteases , cytokine , biology , innate immune system , inflammation , immune system , chemistry , signal transduction , immunology , biochemistry , cd8 , perforin , enzyme , in vitro
Granzymes are serine proteases that, upon release from cytotoxic cells, induce apoptosis in tumor cells and virally infected cells. In addition, a role of granzymes in inflammation is emerging. Recently, we have demonstrated that extracellular granzyme K (GrK) potentiates lipopolysaccharide (LPS)-induced cytokine response from monocytes. GrK interacts with LPS, disaggregates LPS micelles, and stimulates LPS-CD14 binding and Toll-like receptor signaling. Here we show that human GrA also potentiates cytokine responses in human monocytes initiated by LPS or Gram-negative bacteria. Similar to GrK, this effect is independent of GrA catalytic activity. Unlike GrK, however, GrA does not bind to LPS, has little influence on LPS micelle disaggregation, and does not augment LPS-CD14 complex formation. We conclude that GrA and GrK differentially modulate LPS-Toll-like receptor signaling in monocytes, suggesting functional redundancy among cytotoxic lymphocyte proteases in the anti-bacterial innate immune response.