|Budget Amount *help
¥3,600,000 (Direct Cost : ¥3,600,000)
Fiscal Year 1998 : ¥1,300,000 (Direct Cost : ¥1,300,000)
Fiscal Year 1997 : ¥2,300,000 (Direct Cost : ¥2,300,000)
Adrenomedullin (AM) is a novel vasorelaxant peptide identified in pheochromocytome tissue. AM has been shown to be actively produced iii vascular smooth muscle cells (VSMC) and endothelial cells (EC). AM production in VSMC is augmented by the stimulation of TNF-alpha, IL-1beta, lipopolysaccharide (LPS) and glucocorticoid. Regulation of AM production in EC was principally similar to that of VSMC, and lysophosphatidylcholine and oxidized LDL increased AM production in EC.As AM inhibits proliferation of VSMC, AM is expected to suppress atherosclerosis.
As extra-vascular cells, we examined 3 fibroblast and 3 monocyte/macrophage cell lines. All of these cells produced AM.Especially, human fibroblasts secreted AM at a high. Regulation of AM production in fibroblasts is principally similar to that of VSMC.Since Swiss 3T3 fibroblast expresses AM specific receptors, we examined the effects of AM on this cell line. AM stimulated proliferation of Swiss 3T3 cells, and its potency was comparable to
75% that of 10% fetal calf serum. AM increased IL-6 production 5.5 fold, and its effect was synergistically enhanced by co-administration with TNF-alpha, IL-1beta or LPS.In fact, administration of AM with TNF-alpha elevated IL-6 production nearly 300 fold. The proliferative and stimulatory effect of AM was mediated by the cAMP-protein kinase A system
AM is produced in monocyte/macrophage, but their secretion rates were lower than that of VSMC and fibroblasts. AM production in monocyte/macrophage was increased according to their differentiation into macrophages. TNF-alpha, IL-1beta and LPS stimulated AM production, and these substances often elicited synergistic effects when administered with phorbol ester and retinoic acid. IFN-gamma increased but glucocorticoid suppressed AM production, which showed the sharp contrast to the regulation in EC and VSMC.AM inhibited LPS-stimulated TNF-alpha and 1L-6 production 20-50%. These results indicate that AM inhibits inflammatory responses of the monocyte/macrophage.
By this project, AM is found to be produced in variety of cells in response to the inflammatory stimuli. The present results suggest that AM participates in the regulation of inflammation and atherosclerosis as an inhibitory factor. Less