title: Granzymes A and K differentially potentiate LPS-induced cytokine response.
abstract: 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.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Annette C
authors.initials: AC
authors.lastname: Wensink
authors.affiliation: Department of Pathology, University Medical Center Utrecht , Utrecht 3584 CX, The Netherlands.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Kok
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht , Utrecht 3584 CX, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Meeldijk
authors.affiliation: Department of Pathology, University Medical Center Utrecht , Utrecht 3584 CX, The Netherlands.
authors.forename: Job
authors.initials: J
authors.lastname: Fermie
authors.affiliation: NorthShore University Health Systems Research Institute and University of Chicago , Evanston, IL, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Froelich
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht , Utrecht 3584 CX, The Netherlands.
authors.forename: C Erik
authors.initials: CE
authors.lastname: Hack
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Bovenschen