ADRENOMEDULLIN PRODUCTION IN FIBROBLASTS - ITS POSSIBLE FUNCTION AS AGROWTH-REGULATOR OF SWISS 3T3 CELLS

In addition to endothelial cells and vascular smooth muscle cells, we demonstrated that adrenomedullin (AM) is synthesized and secreted from fibroblasts, Swiss 3T3, Hs68, and NHLF cells, in a native and biologi cally active form. Synthesis and secretion of;AM from these fibroblast s was regulated by inflammatory cytokines, such as tumor necrosis fact or and interleukin-l, lipopolysaccharide, growth and differentiation f actors, and hormones in a manner similar to that of vascular smooth mu scle cells and endothelial cells. Tumor necrosis factor-alpha, interle ukin-1 beta, and dexamethasone elevated AM secretion, whereas transfor ming growth factor-beta 1 and interferon-gamma suppressed it in these three fibroblasts, Swiss 3T3 cells were shown to express receptors spe cific for ARI by both cAMP production and receptor binding assay, and AM was found to stimulate DNA synthesis of quiescent cells through the cAMP-mediated pathway. AM secreted from Swiss 3T3 cells was also conf irmed to augment cAMP production and DNA synthesis in the cells themse lves. These effects were inhibited by a neutralizing monoclonal antibo dy against AM. These findings raise the possibility that AM functions as a growth regulator in the case of Swiss 3T3 cells. As AM receptors are widely distributed, AM secreted from fibroblast may play a role as a local regulator in mesenchymal cells of inflammatory of wounded reg ions.