Granzyme K synergistically potentiates LPS-induced cytokine responses in human monocytes

Granzymes are serine proteases released by cytotoxic lymphocytes to induce apoptosis in virus-infected cells and tumor cells. Evidence is emerging that granzymes also play a role in controlling inflammation. Granzyme serum levels are elevated in patients with autoimmune diseases and infections, incl...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2014-04, Vol.111 (16), p.5974-5979
Main Authors: Wensink, Annette C., Kemp, Vera, Fermie, Job, Laorden, M. Isabel García, van der Poll, Tom, Hack, C. Erik, Bovenschen, Niels
Format: Article
Language:English
Subjects:
Animals
Autoimmune diseases
Bacteria
Biological Sciences
Catalysis
Cytokines
Cytokines - metabolism
Cytotoxicity
Gram negative bacteria
Gram-Negative Bacteria - drug effects
Gram-Negative Bacteria - metabolism
Gram-Negative Bacterial Infections - blood
Granzymes - blood
Granzymes - metabolism
Humans
Infections
Inflammation Mediators - metabolism
Lipopolysaccharide Receptors - metabolism
Lipopolysaccharides
Lipopolysaccharides - pharmacology
Low back pain
Mice
Micelles
Monocytes
Monocytes - drug effects
Monocytes - metabolism
Monocytes - secretion
Peptides
Protein Binding - drug effects
Sepsis
Sepsis - blood
Sepsis - microbiology
T lymphocytes
Tumor Necrosis Factor-alpha - secretion
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Summary:Granzymes are serine proteases released by cytotoxic lymphocytes to induce apoptosis in virus-infected cells and tumor cells. Evidence is emerging that granzymes also play a role in controlling inflammation. Granzyme serum levels are elevated in patients with autoimmune diseases and infections, including sepsis. However, the function of extracellular granzymes in inflammation largely remains unknown. Here, we show that granzyme K (GrK) binds to Gram-negative bacteria and their cell-wall component lipopolysaccharide (LPS). GrK synergistically enhances LPS-induced cytokine release in vitro from primary human monocytes and in vivo in a mouse model of LPS challenge. Intriguingly, these extracellular effects are independent of GrK catalytic activity. GrK disaggregates LPS from micelles and augments LPS–CD14 complex formation, thereby likely boosting monocyte activation by LPS. We conclude that extracellular GrK is an unexpected direct modulator of LPS–TLR4 signaling during the antimicrobial innate immune response.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1317347111