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.
Highlights
Granzymes are a family of structurally related serine proteases best known for their ability to induce apoptosis in tumor cells or virus-infected cells.[1]
In contrast to granzyme K (GrK), granzyme A (GrA) does not bind to LPS, does not efficiently remove LPS molecules from micelles, and does not augment LPS-CD14 complex formation
To determine the impact of GrA on LPS-induced cytokine responses, monocytes were incubated with extracellular GrA or its catalytically inactive mutant (GrA-SA) in the presence or absence of a suboptimal stimulatory dose of LPS
Summary
Granzymes are a family of structurally related serine proteases best known for their ability to induce apoptosis in tumor cells or virus-infected cells.[1] There are five human granzymes: granzyme A (GrA), GrB, GrH, GrK, and GrM. Granzymes are stored in granules of cytotoxic lymphocytes (including cytotoxic T lymphocytes, natural killer (NK) cells, NKT cells, and γδ T cells) and are released into the immunological synapse upon recognition of a target cell by a cytotoxic lymphocyte. Increased levels of soluble granzymes are found in plasma and synovial fluid of rheumatoid arthritis patients[7,8] and in serum and broncheoalveolar lavage fluid of patients suffering from bacterial or viral infections.[8,9,10,11,12]
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