Interleukin-1β and interleukin-4 increase parathyroid hormone—related protein secretion by human umbilical vein endothelial cells in culture,

OBJECTIVE: Our purpose was to learn whether cytokines such as interleukin-1β and related (or antagonistic) cytokines, hormones, and growth factors could regulate secretion of the vasorelaxant parathyroid hormone—related protein in human umbilical vein endothelial cells in culture. STUDY DESIGN: Secondary cultures of human umbilical vein endothelial cells were grown to confluence and treated with interleukin-1β, an array of factors with possible regulatory actions (cytokines, growth factors, vasoactive peptides, and steroids), and a phorbol ester as a stimulatory control. After 24 hours immunoreactive parathyroid hormone—related peptide in the media was measured by a two-site sandwich radioimmunoassay. The mechanism of interleukin-1β action was probed with interleukin-1β receptor antagonist and selected inhibitors. RESULTS: Interleukin-1β (10 ng/ml) produced up to an eightfold increase in parathyroid hormone—related peptide secretion from human umbilical vein endothelial cells in culture (p< 0.01). Half-maximal stimulation was sen at 0.23 ng/ml. Interleukin-1 receptor antagonist, cycloheximide, and actinomycin D blocked the effects of interleukin-1β (p< 0.05). Interleukin-4 at 10 ng/ml and phorbol 12-myristate 13-acetate at 10−7 mol/L significantly increased the secretion of parathyroid hormone—related peptide by human umbilical vein endothelial cells (p< 0.05). The time course of each interleukin showed an effect beyond 12 hours. The effects of interleukin-1β and interleukin-4 appeared to be specific, because a large series of related interleukins and other growth factors and cytokines were without effect. CONCLUSION: Interleukin-1β and interleukin-4 increase parathyroid hormone—related protein secretion in human umbilical vein endothelial cells in culture. Because interleukin-1β messenger ribonucleic acid has been found in umbilical cord endothelial cells, we propose that the umbilical cord has a novel vasorelaxant regulatory system that uses interleukin-1β endothelial action and secretion of the vasorelaxant parathyroid hormone—related peptide.