thromboxane-b2 and Leukemia--Myeloid

U46619, a thromboxane A2 (TXA2) mimetic, inhibits human monocyte chemotactic responses, suggesting that TXA2, an arachidonic acid metabolite, may alter monocyte adhesion. We tested the hypothesis that TXA2 alters Lipopolysaccharide (LPS)-induced adhesion of THP-1 cells, a human monocytic leukemia cell line. Salmonella enteritidis endotoxin (1 microgram/mL) induced a significant (p < .05; n = 6) increase in the adherence of THP-1 cells (basal, 5.7 +/- 1.8 micrograms/well; LPS, 78.8 +/- 4.9 micrograms/well). Treatment of THP-1 cells with indomethacin or TXA2 receptor antagonists before LPS stimulation significantly (p < .05) enhanced adhesion, suggesting that endogenously produced TXA2 or prostaglandins alter LPS-induced THP-1 cell adhesion. TXA2 mimetics significantly decreased (p < .05; n = 5 and n = 3, respectively) LPS-induced THP-1 cell adhesion. This effect was blocked by three structurally dissimilar TXA2 receptor antagonists. These results support the hypothesis that TXA2 alters LPS-induced adhesion of THP-1 cells.

Topics: Cell Adhesion; Cyclic AMP; Humans; Leukemia, Myeloid; Lipopolysaccharides; Radioligand Assay; Receptors, Thromboxane; Thromboxane B2; Tumor Cells, Cultured

We studied the regulation of thromboxane (TX) synthesis in promyelocytic leukemia cells during macrophage differentiation. Cells treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) showed rates of TXB2 synthesis from exogenous arachidonic acid that exceeded that of control cells by a factor of up to 81. Cells treated with sn-1,2-dioctanoylglycerol (diC8) showed similarly high TXB2 synthesis rates when diC8 was added concomitantly with a subthreshold concentration of TPA or when given in multiple doses. These activities depended on de novo synthesis of prostaglandin H (PGH) synthase because: microsomal PGH synthase activity showed large increases in Vmax values, and mass measurements of PGH synthase revealed the presence of PGH synthase in differentiating cells whereas the enzyme was undetectable in control cells. These results indicate that macrophage differentiation is associated with stimulation of TXB2 synthesis that requires both activation of protein kinase C and de novo synthesis of PGH synthase.

Topics: Arachidonic Acid; Arachidonic Acids; Calcimycin; Cell Differentiation; Cell Line; Diglycerides; Glycerides; Humans; Kinetics; Leukemia, Myeloid; Macrophages; Prostaglandin-Endoperoxide Synthases; Protein Kinase C; Tetradecanoylphorbol Acetate; Thromboxane B2; Trifluoperazine

Bleeding and abnormal platelet aggregation occur in patients with myeloproliferative disorders. In this study, twenty patients were examined, some sequentially, and a proportion found to have defective aggregation toward adrenaline, adenosine diphosphate (ADP), and collagen. In these seven patients, the abnormality in platelet response with defective collagen-induced [14C]serotonin release correlated with poor collagen-stimulated thromboxane B2 (TXB2) production. In contrast, five of these patients showed a normal threshold aggregation response to arachidonic acid. The combined results suggest that in these patients, there is a defect between receptor-stimulus coupling and the mobilization of arachidonic acid from membrane phospholipid.

Topics: Blood Platelets; Humans; Leukemia, Myeloid; Membrane Lipids; Myeloproliferative Disorders; Platelet Aggregation; Platelet Count; Polycythemia Vera; Serotonin; Syndrome; Thrombocytosis; Thromboxane B2