Interleukin-1, Tumor Necrosis Factor and Lipopolysaccharide Additively Stimulate Production of Adrenomedullin in Vascular Smooth Muscle Cells

To elucidate physiological functions of adrenomedullin (AM) secreted from vascular smooth muscle cells (VSMCs), we examined the effect of cytokines, growth factors and related substances on AM production in cultured rat VSMC. Among them, interleukin-1α (IL-1α), IL-1β, tumor necrosis factor-α (TNF-α) and TNF-β, as well as lipopolysaccharide (LPS), markedly augmented production and gene expression of AM. Although maximal stimulation levels of these substances were not greatly different, ED 50 values of IL-1s (0.3 ng/ml) were about 1/10 that of TNFs and LPS. AM mRNA levels maximized at 3-6 h after stimulation with IL-1β and LPS, while TNF-α increased the AM mRNA level up to 48 h. Furthermore, IL-1α, TNF-α and LPS additively increased AM production in VSMC. AM production was slightly augmented by fibroblast, epidermal and platelet derived growth factors. These results suggest that AM secreted from VSMC actually exerts a vasorelaxant effect under physiological conditions such as endotoxin shock, atherosclerosis and inflammation.