Activation of human granulocyte type 1-prophospholipase A2.
Using an assay for measurement of released type 1-prophospholipase A2 (type 1-proPLA2) propeptides (PROP assay), we have shown that human granulocytes, but not lymphocytes or macrophages, abundantly express this 'pancreatic' type 1-proPLA2 zymogen. Stimulation with tumour necrosis factor-alpha (TNF-alpha) and other cytokines results in the immediate release from granulocytes of a mixture of free propeptides and type 1-proPLA2 precursor. We also found that granulocytes contain an approximately 29 kDa trypsin-like endogenous type 1-proPLA2 activator. PROP assay and TAP (trypsinogen activation peptide) assay of plasma samples accurately predicts the segregation of acute pancreatitis into three clearly defined categories of severity--mild, intermediate and severe--at the time of first hospital admission and over the next few hours of observation. Mild and intermediate pancreatitis are associated with a degree of granulocyte stimulation limited to the release of the unactivated type 1-proPLA2 precursor. Progression to severe disease is accompanied by the activation of granulocyte type 1-proPLA2, apparently carried to completion. This identifies the approximately 29 kDa endogenous activator of type 1-proPLA2 in granulocytes as a critical mediator at a threshold stage in acute pancreatitis, which marks the transition from uncomplicated pancreatitis to the potentially lethal disease. Specific inhibitors of this key regulatory enzyme modelled on the P3-P1 domain of the type 1-proPLA2 activation peptide would seem to be promising candidates for a new class of chemotherapeutic agents.
Rae
D
D
Dept. of Surgery, St George's Hospital Medical School, London, UK.
Beechey-Newman
N
N
Burditt
L
L
Sumar
N
N
Hermon-Taylor
J
J
D004789:Enzyme Activation; D004792:Enzyme Precursors; D006098:Granulocytes / Q000201:enzymology*; D006801:Humans; D010195:Pancreatitis / Q000097:blood / Q000503:physiopathology*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D011498:Protein Precursors / Q000378:metabolism*; D021382:Protein Sorting Signals
D004792:Enzyme Precursors; D011498:Protein Precursors; D021382:Protein Sorting Signals; D010741:Phospholipases A; D054467:Phospholipases A2; C085333:prophospholipase A2