INTERLEUKIN-1-BETA 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 interleu kin-lp and related (or antagonistic) cytokines, hormones, and growth f actors could regulate secretion of the vasorelaxant parathyroid hormon e-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-1 beta, a n 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 hormon e-related peptide in the media was measured by a two-site sandwich rad ioimmunoassay. The mechanism of interleukin-1 beta action was probed w ith interleukin-1 beta receptor antagonist and selected inhibitors. RE SULTS: Interleukin-1 beta (10 ng/ml) produced up to an eightfold incre ase in parathyroid hormone-related peptide secretion from human umbili cal vein endothelial cells in culture (p < 0.01). Half-maximal stimula tion was seen at 0.23 ng/ml. Interleukin-1 receptor antagonist, cycloh eximide, and actinomycin D blocked the effects of interleukin-1 beta ( p < 0.05). Interleukin-4 at 10 ng/ml and phorbol 12-myristate 13-aceta te at 10(-7) mol/L significantly increased the secretion of parathyroi d 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-1 beta and interleukin-4 appeared to be specific, because a large series of related interleukins and ot her growth factors and cytokines were without effect. CONCLUSION: Inte rleukin-1 beta and interleukin-4 increase parathyroid hormone-related protein secretion in human umbilical vein endothelial cells in culture . Because interleukin-1 beta messenger ribonucleic acid has been found in umbilical cord endothelial cells, we propose that the umbilical co rd has a novel vasorelaxant regulatory system that uses interleukin-1 beta endothelial action and secretion of the vasorelaxant parathyroid hormone-related peptide.