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 f rom vascular smooth muscle cells (VSMCs), we examined the effect of cy tokines, growth factors and related substances on AM production in cul tured rat VSMC. Among them, interleukin-1 alpha (IL-1 alpha), IL-1 bet a, tumor necrosis factor-alpha (TNF-alpha) and TNF-beta, as well as li popolysaccharide (LPS), markedly augmented production and gene express ion of AM. Although maximal stimulation levels of these substances wer e 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 st imulation with IL-1 beta and LPS, while TNF-alpha increased the AM mRN A level up to 48 h. Furthermore, IL-1 alpha, TNF-alpha and LPS additiv ely increased AM production in VSMC. AM production was slightly augmen ted by fibroblast, epidermal and platelet derived growth factors. Thes e results suggest that AM secreted from VSMC actually exerts a vasorel axant effect under physiological conditions such as endotoxin shock, a therosclerosis and inflammation. (C) 1995 Academic Press, Inc.