The role of the endothelial cell in leukotriene biosynthesis

Endothelial cells do not contain 5-lipoxygenase and thus are unable to generate LTA4 from arachidonate. Nonetheless, endothelial cells may play an important role in leukotriene synthesis by virtue of their ability to metabolize LTA4 derived from activated polymorphonuclear leukocytes (PMNL) and to modulate PMNL 5-lipoxygenase activity. Porcine aortic endothelial cells were found to metabolize exogenous LTA4 to LTC4, and under some conditions human umbilical vein endothelial cells have been found to generate LTB4. Production of LTB4 by these cells appears to be under poorly understood cellular control, and it remains a controversial area of research. Under physiologic conditions, endothelial cells are in constant contact with circulating PMNL, which are known to generate substantial amounts of LTA4. When these two cell types are coincubated in vitro, clear evidence of transcellular metabolism of PMNL-derived LTA4 to LTC4 by endothelial cells is found. Coincubations produce from two to greater than 10 times more LTC4 than either cell alone. In contrast to these findings, when these cells were activated by the receptor-mediated agonist fMLP, evidence for an endothelial cell inhibition of PMNL 5-lipoxygenase was obtained. Rather than augmentation of LTC4 production, as seen with A23187 activation, coincubation activated by fMLP generated significantly less LTC4 (0.23 +/- 0.08 versus 0.75 +/- 0.39 pmol/10(7) cells). The endothelial cell inhibition was removed when these cells were pretreated with aspirin, suggesting that their major cyclooxygenase product, prostacyclin, acts as a feedback regulator of LT synthesis. When cyclooxygenase was blocked, significant transcellular LTC4 synthesis was once again apparent (1.66 +/- 0.44 pmol/10(7) cells).