Abstract
The blood coagulation factor, human thrombin has been shown to have chemotactic and mitogenic effects on mononuclear phagocytic inflammatory cells. In the present study, we have use the U937 human monocytic cell line to explore the signal transduction mechanisms utilised by thrombin in these cells. In U937 cells differentiated into a macrophage-like phenotype. thrombin stimulated the formation of inositol trisphosphate (IP 3) and the mobilisation of intracellular Ca 2+ ([Ca 2+] i) via a mechanism which was partially sensitive to pertussis toxin. Thrombin failed, however, to evoke thromboxane (Tx)B 2 synthesis in the differentiated cells. In contrast, the chemotactic peptide N-formy-L-methionylleucyl-L-phenylalanine (FMLP) stimulated TxB 2 synthesis under conditions where it evoked increases in IP 3 formation and [Ca 2+] i mobilisation, via a pertussis toxin-sensitive mechanism, comparable in extent to those mediated by thrombin. Thrombin also failed to cause inhibitory guanine nucleotide binding protein (G i)-mediated inhibition of adenylate cyclase activity in U937 cell membranes. Those results indicate that U937 cells express receptors for thrombin which are in part coupled via a pertussis toxin-sensitive guanine nucleotide binding protein to phospholipase C activation, the formation of IP 3 and the mobilisation of [Ca 2+ i. However, the failure of thrombin to stimulate TxB 2 synthesis or cause G i-mediated inhibition of adenylate cyclase in U937 cells contrasts with its effects in human platelets and other thrombin-responsive cells. These results suggest that the thrombin receptor or receptor-effector coupling mechanism(s) in mononuclear cells is functionally distinct from the thrombin receptor or receptor-effector coupling mechanism(s) present in other thrombin-responsive cells.
Published Version
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